Oxadiazole derivatives and drugs containing these derivatives as the active ingredient

ABSTRACT

An oxadiazole derivative of formula (I) and a non-toxic salt thereof, 
                         
wherein R is hydrogen, alkyl, CycA, etc.; AA 1  is a single bond, amino acid residue, etc.; AA 2  is a single bond, amino acid residue, etc.; R 7  and R 8  are hydrogen, alkyl, etc.; R 9  is hydrogen, alkyl, etc. R 10  is hydrogen, alkyl, etc.).

This application is a 371 of PCT/JP00/08514 filed Dec. 1, 2000.

TECHNICAL FIELD

The present invention relates to an oxadiazole derivative.

Specifically, the present invention relates to;

-   1) an oxadiazole derivative of formula (I),

wherein all symbols have the same meanings as hereafter, and a non-toxicsalt thereof,

-   2) a method for the preparation thereof and-   3) a pharmaceutical agent comprising the oxadiazole derivative and    non-toxic salt thereof as active ingredient.

BACKGROUND

Cysteine protease is a generic name of proteases which have a cysteineresidue in the activity center and catalyze protein degradation thereat.In animal cells, a large number of cysteine proteases are known; forexample, cathepsin family, calpain family, caspase-1, etc. Cysteineprotease exists in various kinds of cells extensively and plays a basicand essential role in the homeostasis, such as conversion (processing)of precursor protein into its active form and degradation of proteinswhich have become out of use, etc. Until now, its physiological effectsare being vigorously studied, and as the studies progress andcharacteristics of the enzymes are revealed, cysteine protease came tobe taken as a cause of really various kinds of diseases.

It is revealed that cathepsin S (See J. Immunol., 161, 2731 (1998)) andcathepsin L (See J. Exp. Med., 183, 1331 (1996)) play a role inprocessing of major histocompatibility antigen class-II in antigenpresenting cells which play an important role in the early stage ofimmune responses. In an experimental inflammatory response model inducedby antigens, a specific inhibitor of cathepsin S showed an inhibitoryeffect (see J. Clin. Invest., 101, 2351 (1998)). It is also reportedthat in a leishmania-infected immune response model cathepsin Binhibitor inhibited an immune response and by means of this effect itinhibited the proliferation of protozoans (See J. Immunol., 161, 2120(1998)). In vitro, a result is given that a calpain inhibitor and acysteine protease inhibitor E-64 inhibited apoptosis which is induced bystimuli on T cell receptors (see J. Exp. Med., 178, 1693 (1993)).Therefore, it is conceivable that cysteine protease is much concernedwith the progress of immune responses.

It is speculated that caspase-1 or a cysteine protease similar theretooccupies an important position in the mechanism of cell death includingapoptosis. Therefore it is expected for a cysteine protease inhibitor tobe used as an agent for the prophylaxis and/or treatment of thosediseases concerning apoptosis, such as infectious diseases,deterioration or sthenia of immune function and brain function, tumors,etc. Diseases concerning apoptosis are, acquired immune deficiencysyndrome (AIDS), AIDS-related complex (ARC), adult T cell leukemia,hairy cell leukemia, spondylopathy, respiratory apparatus disorder,arthitis, HIV or HTLV-1 related diseases such as uveitis, virus-relateddiseases such as hepatitis C, cancer, collagenosis (systemic lupuserythematosus, rheumatoid arthritis, etc.), autoimmune diseases(ulcerative colitis, Sjögren's syndrome, primary biliary cirrhosis,spontaneous thrombocytopenic purpura, autoimmune hemolytic anemia,myasthenia gravis, insulin dependent (type I) diabetes, etc.), diseasesaccompanied by thrombocytopenia (osteomyelodysplasia syndrome, periodicthrombocytopenia, aplastic anemia, spontaneous thrombocytopenia,disseminated intravascular coagulation (DIC), etc.), hepatic diseasessuch as viral hepatitis (type C, A, B, F, etc.) or hepatitismedicamentosus and cirrhosis, dementia (Alzheimer's diseases,Alzheimer's senile dementia, etc.), cerebrovascular injury, nervedegeneration diseases, adult acute respiratory distress syndrome,infectious diseases, prostatomegaly, hysteromyoma, bronchial asthma,arteriosclerosis, all kinds of lusus naturae, nephropathy, senilecataract, chronic fatigue syndrome, myodystrophy, peripheral neuropathy,etc.

Moreover, caspase-1 is concerned with various inflammatory diseases andthose diseases caused by immune disorders, by means of interleukin-1β(IL-1β) production. A lot of diseases are shown to be involved withcaspase-1 including inflammatory diseases and autoimmune diseases listedbelow; inflammatory bowel diseases such as ulcerative colitis,insulin-dependent (type-I) diabetes, autoimmune thyroid diseases,infectious diseases, rejection of an organ transplantation, graft versushost diseases, psoriasis, periodontitis (above, see N. Eng. J. Med.,328, 106 (1993)), pancreatitis (see J. Interferon Cytokine Res., 17, 113(1997)), hepatitis (see J. Leuko. Biol., 58, 90 (1995)),glomerulonephritis (see Kidney Int., 47, 1303 (1995)), endocarditis (seeInfect. Immun., 64, 1638 (1996)), myocarditis (see Br. Heart J., 7, 561(1995)), systemic lupus erythematosus (see Br. J. Rheumatol., 34, 107(1995)), Hashimoto's diseases (see Autoimmunity, 16, 141 (1993)), etc.),etc. Experimentally, it is reported that in liver injury model inducedby lipopolysaccharide and D-galactosamine, a caspase-1 inhibitordepressed the symptoms, and it is expected that a caspase inhibitorshows an effect in sepsis, ischemic reperfusion and hepatitis gravis(see Am. J. Respir. Crit. Care Med., 159, 1308 (1999)).

It is also shown that cysteine protease is concerned with rheumatoidarthritis. IL-1β is shown to be concerned with this disease (seeArthritis Rheum., 39, 1092 (1996)), and in addition, as autoantibodytoward calpastatin (endogenous calpain inhibitor) was found in the serumof the patients, it is considered that increase of calpain activityleads to the cause of diseases.

It is also known that cysteine protease causes a disease symptom bydecomposing various proteins which compose the organism.

It is reported that cathepsin B plays a role in decomposing muscularprotein in the chronic phase of sepsis (see J. Clin. Invest., 97, 1610(1996)), and in decomposing muscular protein in myodystrophy model (seeBiochem. J., 288, 643 (1992)). And it is also reported that calpaindecomposes the myocyte cells protein of myodystrophy patients (see J.Biol. Chem., 270, 10909 (1995)).

In the ischemic reperfusion model, a result is given that calpain causesdegeneration of brain tissues by means of degradation of protein kinaseC-β (see J. Neurochem., 72, 2556 (1999)) and that a cathepsin Binhibitor inhibits nerve injury (see Eur. J. Neurosci., 10, 1723(1998)).

In the brain ischemic model, it is known that the degradation ofspectrin by calpain causes a damage and function disorder in theneurocyte (see Brain Res., 790, 1(1998)) and it is reported that anIL-1β receptor antagonist relieved the symptoms (see Brain Res. Bull.,29, 243 (1992)).

In myocardial ischemic model it is confirmed that cathepsin B activityincreases in the lesion (see Biochem. Med. Metab. Biol., 45, 6 (1991)).

In the experiment utilizing ischemic liver injury model, it proved thatnecrosis and apoptosis of hepacyte were induced by means ofprotein-decomposing activity of calpain (see Gastroenterology, 116, 168(1999)).

Besides, it is known that calpain causes cornea turbid in cataract bymeans of degradation of crystalline (see Biol. Chem., 268, 137 (1993))and that in the lesion of contracted gut mucosa model it was confirmedthat the activity of cathepsin B, H and L increased (see JPEN. J.Parenter. Enteral. Nutr., 19, 187 (1995)) and it is shown that cysteineprotease is a cause of the diseases resulting from such proteindegradation.

It has been revealed that cysteine protease is concerned with systemicdisorders of organs and tissues by shock.

It is shown that IL-1β is concerned with septic shock and systemicinflammatory response syndrome (see Igakuno Ayumi, 169, 850 (1994)) andbesides, it is reported that in endotoxin shock model induced bylipopolysaccharide, a calpain inhibitor prevented circulatory systemdisorder, disorders of liver and pancreas and acidosis by means ofinhibitory effect of activation of nuclear factor κB (see Br. J.Pharmacol., 121, 695 (1997)).

Since it is reported that calpain is concerned with platelet coagulationprocess and a calpain inhibitor prevented the coagulation of platelets(see Am. J. Physiol., 259, C862 (1990)), it is conceivable that acysteine protease inhibitor is useful for the disorder by bloodcoagulation. From the fact that calpain activity increased in the serumof the patients of purpura (thrombocytopenia) resulting from marrowtransplantation, it is conceivable that calpain is concerned with theactual disease symptoms (see Bone Marrow Transplant., 24, 641 (1999)).Caspase-1 inhibitor inhibited the apoptosis of blood vessel endothelialcells, which is seen in the early phase of purpura (thrombocytopenia)and is thought to be important for the progression of the pathologyafterwards (see Am. J. Hematol., 59, 279 (1998)), so it is expected thata cysteine protease inhibitor makes effect on purpura and hemolyticuremic syndrome.

The effect of cysteine protease and its inhibitor is being investigatedin the field of cancer and metastasis of cancer.

Since the proliferations of pancreas cancer cells (see Cancer Res., 59,4551 (1999)) and acute myeloid leukemia cells (see Clin. Lab. Haematol.,21, 173 (1999)) were inhibited by an inhibitor or receptor antagonist ofcaspase-1, it is expected that caspase-1 activity is essential for theprocess of proliferation of tumor cells, and that an inhibitor thereofis effective for these cancers. Cathepsin B activity increased in coloncancer metastasis model (see Clin. Exp. Metastasis, 16, 159 (1998)).Cathepsin K protein expression was recognized in human breast cancercells and the relationship of cathepsin K and bone metastasis is shown(Cancer Res., 57, 5386 (1997)). Also, a calpain inhibitor inhibitedmigaration of the cells and it implied the possibility that calpaininhibition may inhibit metastasis of cancer (J. Biochem., 272, 32719(1997)). From these, a cysteine protease inhibitor is presumed to showan inhibitory effect on the metastasis of various malignant tumors.

As to AIDS (see AIDS, 10, 1349 (1996)) and AIDS-related complex (ARC)(see Arch. Immunol. Ther. Exp. (Warsz), 41, 147 (1993)), it is shownthat IL-1 is concerned with the progress of symptoms, so it isconceivable that cysteine protease inhibition leads to an effectivetherapy of AIDS and its complication.

Some parasites have cysteine protease activity in their body. Cysteineprotease in the phagosome of malaria protozoan is an essential enzymefor supplying nutrition of the parasites. A result is given that theinhibitor of cysteine protease shows an inhibitory effect of theproliferation of the protozoan (see Blood, 87, 4448 (1996)). Thus, it ispossible to apply the inhibitor of cysteine protease to malaria.

In Alzheimer-type dementia, it is said that adhesion ofnon-physiological protein called amyloid to brain is deeply involvedwith nervous function disorders. Cysteine protease has an activity ofgenerating amyloid by decomposing its precursor protein. Clinically, itis shown that cathepsin B is an enzyme that possesses a processingactivity of amyloid proteins in the brains of Alzheimer-type dementiapatients (see Biochem. Biophys. Res. Commun., 177, 377 (1991)). Also,expressions of cathepsin B protein (see Virchows Arch. A. Pathol. Anat.Histpathol., 423, 185 (1993)), cathepsin S protein (see Am. J. Pathol.,146, 848 (1995)) and calpain protein (see Proc. Natl. Acad. Sci. USA,90, 2628 (1993)) and increase of caspase-1 activity (see J. Neuropathol.Exp. Neurol., 58, 582 (1999)) were confirmed in the brain lesions.Besides, by the fact that calpain is concerned with the formation ofpaired helical filaments which accumulate in Alzheimer dementia patientsand production of protein kinase C which stabilizes the protein byphosphorylation (see J. Neurochem., 66, 1539 (1996)) and by theknowledge that caspase is concerned with neurocyte death by β amyloidprotein adhesion (see Exp. Cell Res., 234, 507 (1997)), it is impliedthat cysteine protease is concerned with the disease symptoms.

As to Huntington's chorea, cathepsin H activity increased in thepatient's brain (see J. Neurol. Sci., 131, 65 (1995)), and the ratio ofactivated form of calpain increased (see J. Neurosci., 48, 181 (1997)).In Parkinson's diseases, the increase of expression of m-calpain wasrecognized in the mesencephalon of the patients (see Neuroscience, 73,979 (1996)) and IL-1β protein was expressed in brain (see Neurosci.Let., 202, 17 (1995)). Therefore, it is speculated that cysteineprotease is concerned with the genesis and progress of these diseases.

Besides, in the central nervous system, spectrin degradation by calpainis found in the process of injury on neurocyte observed in the traumaticbrain injury model (see J. Neuropathol. Exp. Neurol., 58, 365 (1999)).

In spinal cord injured model it was recognized that in glia cellscalpain messenger RNA increased and its activity increased in the lesionand the possibility was shown that calpain had much to do with thedegeneration of myelin and actin after injury (see Brain Res., 816, 375(1999)). And IL-1β was shown to be concerned with the genesis ofmultiple sclerosis (see Immunol. Today, 14, 260 (1993)). Therefore, itis conceivable that a cysteine protease inhibitor is promising as anagent for the treatment of these nerve-injuring diseases.

Normally, cathepsin S and cathepsin K do not exist in human arterialwalls but it was confirmed that they expressed in arterial sclerosislesion and they had an decomposing activity of alveolus elastica (see J.Clin. Invest., 102, 576 (1998)) and a calpain inhibitor and antisense ofm-calpain inhibited the proliferation of human blood vessel smoothmuscle cells and it is shown that m-calpain is concerned with theproliferation of smooth muscle (see Arteioscler. Thromb. Vssc. Biol.,18, 493 (1998)), so it is conceivable that a cysteine protease inhibitoris promising for the treatment of blood vessel lesion such asarteriosclerosis, restenosis after percutaneous transluminal coronaryangioplasty (PTCA), etc.

It is reported that in liver, cathepsin B is activated in the process ofinjuring hepatocyte by bile acid (see J. Clin. Invest., 103, 137 (1999))and so it is expected that a cysteine protease inhibitor is effectivefor cholestatic cirrhosis.

In lungs and respiratory system, it is shown that cathepsin S is anenzyme that plays a role in elastin degradation by alveolus macrophages(see J. Biol. Chem., 269, 11530 (1994)), so it is probable that cysteineprotease is a cause of pulmonary emphysema. And it is also shown thatlung injury (see J. Clin. Invest., 97, 963 (1996)), lung fibrosis (seeCytokine, 5, 57 (1993)) and bronchial asthma (see J. Immunol., 149, 3078(1992)) are caused by production of IL-1β by caspase-1.

It is pointed out that cysteine protease is also concerned with diseasesconcerning bones and cartilages. Cathepsin K is specifically recognizedin osteoclast and it has a decomposing activity against bone matrix (seeJ. Biol. Chem., 271, 12517 (1996)), so its inhibitor is expected to showan effect against osteoporosis, arthritis, rheumatoidarthritis,osteoarthritis, hypercalcemia and osteometastasis of cancer, wherepathologic bone resorption is recognized. And since IL-1β is shown to beconcerned with bone resorption and cartilage degradation, and acaspase-1 inhibitor and IL-1β receptor antagonist inhibit the boneresorption and symptoms of arthritis, a caspase-1 inhibitor and IL-1βreceptor antagonist are expected to be effective for arthritis (seeCytokine, 8, 377 (1996)) and osteoporosis (J. Clin. Invest., 93, 1959(1994)). And it is reported that IL-1β is also concerned withosteoarthritis (see Life Sci., 41, 1187 (1987)).

Cysteine protease is involved with production of various hormones. Sinceincrease of messenger RNA of cathepsin S was recognized by stimuli ofthytropin on thyroid epitheliocyte strains (see J. Biol. Chem., 267,26038 (1992)), it is conceivable that a cysteine protease inhibitor iseffective for hyperthyrodism.

Since quantity and activity of cathepsin B protein increased in thegingival sulcus liquid of periodontitis patients (see J. Clin.Periodontol., 25, 34 (1998)), it is pointed out that cysteine proteaseis concerned with periodontitis.

Therefore, it is expected that the compound that possesses theinhibitory activity of cysteine protease is useful as an agent for theprophylaxis and/or treatment of inflammatory diseases (periodontitis,arthritis, inflammatory bowel diseases, infectious diseases,pancreatitis, hepatitis, glomerulonephritis, endocarditis, myocarditis,etc.), diseases induced by apoptosis (graft versus host diseases,rejection of an organ transplantation, acquired immune deficiencysyndrome (AIDS), AIDS-related complex (ARC), adult T cell leukemia,hairy cells leukemia, spondylopathy, disorders of respiratory apparatus,arthritis, HIV or HTLV-1 related diseases such as uveitis, virus-relateddiseases such as hepatitis C, cancer, collagenosis (systemic lupuserythematosus, rheumatoid arthritis, etc.), ulcerative colitis,Sjögren's syndrome, primary biliary cirrhosis, spontaneousthrombocytopenic purpura, autoimmune hemolytic anemia, myastheniagravis, autoimmune diseases such as insulin dependent (type I) diabetes,diseases accompanying thrombocytopenia (osteomyelodysplasia syndrome,periodic thrombocytopenia, aplastic anemia, spontaneousthrombocytopenia, disseminated intravascular coagulation (DIC), etc.),hepatic diseases such as viral hepatitis (type A, B, C, F, etc.) orhepatitis medicamentosus and cirrhosis, dementia such as Alzheimer'sdiseases and Alzheimer's senile dementia, cerebrovascular injury, nervedegeneration diseases, adult acute respiratory distress syndrome,infectious diseases, prostatomegaly, hysteromyoma, bronchial asthma,arteriosclerosis, all kinds of lusus naturae, nephropathy, senilecataract, chronic fatigue syndrome, myodystrophy, peripheral neuropathy,etc.), diseases induced by disorders of immune response (graft versushost diseases, rejection of an organ transplantation, allergic diseases(bronchial asthma, atopic dermatitis, allergic rhinitis, pollinosis,diseases induced by house dusts, irritable pneumonia, food allergy,etc.), psoriasis, rheumatoid arthritis, etc.), autoimmune diseases(insulin-dependent (type I) diabetes, systemic lupus erythematosus,Hashimoto's diseases, multiple sclerosis, etc.), disease by degradationvarious proteins which compose the organism (myodystrophy, cataract,periodontitis, hepatocyte disease by bile acid such as cholestaticcirrhosis, etc.), decomposition of alveolus elastica such as pulmonaryemphysema, ischemic diseases (brain ischemia, brain disorders(encephalopathy) by ischemic reperfusion, myocardial infarction,ischemic hepatopathy, etc.), shock (septic shock, systemic inflammatoryresponse syndrome, endotoxin shock, acidosis, etc.), circulatory systemdisorders (arteriosclerosis, restenosis after percutaneous transluminalcoronary angioplasty (PTCA), etc.)), blood coagulation disorders(thrombocytopenic purpura, hemolytic uremic syndrome, etc.), malignanttumor, acquired immune deficiency syndrome (AIDS) and AIDS-relatedcomplex (ARC), parasitic diseases such as malaria, nerve degenerativediseases (Alzheimer-type dementia, Huntington's chorea, Parkinson'sdiseases, multiple sclerosis, traumatic encephalopathy, traumaticspondylopathy, etc.), pulmopathy such as lung fibrosis, bone resorptiondiseases (osteoporosis, rheumatoid arthritis, arthritis, osteoarthritis,hypercalcemia, osteometastasis of cancer, etc.), endocrinesthenia suchas hyperthyroidism.

On the other hand, what is the most important for inhibitors ininhibiting the activity of proteases is, the special reaction site whichinteracts with the amino acid residue that is the activity center ofproteases. The surrounding structure of the reaction sites arerepresented by - - - P3P2P1-P1′P2′P3′ - - - , centering peptide binding(P1-P1′) of the reaction site, and at P1 site there exist amino acidresidues fitting the substance specificity of proteases which theinhibitors aim. Some reaction sites against cysteine proteases areknown, for Example, in the specification of WO99/54317, the followingsare described; P1 position against calpain I, II (norvaline,phenylalanine, etc.),

-   P1 position against calpain I (arginine, lysine, tyrosine, valine,    etc.),-   P1 position against papain (homophenylalanine, arginine, etc.-   P1 position against cathepsin B-homophenylalanine, phenylalanine,    tyrosine, etc.),-   P1 position against cathepsin S (valine, norleucine, phenylalanine,    etc.),-   P1 position against cathepsin L (homophenylalanine, lysine, etc.),-   P1 position against cathepsin K (arginine, homophenylalanine,    leucine, etc.),-   P1 position against caspase (aspartic acid).

On the other hand, in the specification of WO 98/49190, it is disclosedthat the compound of formula (A) or a pharmaceutically acceptable saltthereof has an inhibitory activity against cysteine proteases,

wherein Z^(A) is a cysteine protease binding moiety;

-   X^(A) and Y^(A) are independently S, O or N, said N being optionally    substituted with alkyl or alkenyl optionally substituted with 1–3    halogen atoms, or (C5–C6)aryl, arylalkyl or arylalkenyl optionally    comprising 1–3 heteroatoms selected from N, O and S, and optionally    substituted with halogen atom, cyano, nitro, haloalkyl, amino,    aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy,    haloalkoxy, carboxyl, carboalkoxy, arylcarboxamide, alkylthio or    haloalkylthio;-   R₁ ^(A) is alkyl or alkenyl optionally substituted with 1–3 halo or    hydroxy; alkylamino, dialkylamino, alkyldialkylamino; or cycloalkyl,    alkylcycloalkyl, (C5–C12)aryl, (C5–C12)arylalkyl or    (C5–C12)arylalkenyl optionally comprising 1–4 heteroatoms selected    from N, O and S, and optionally substituted with halo, cyano, nitro,    haloalkyl, amino, aminodialkyl, dialkylamino, alkyl, alkenyl,    alkynyl, alkoxy, haloalkyl, carboxyl, carboalkoxy, alkylcarboxamide,    (C5–C6)aryl, —O—(C5–C6)aryl, arylcarboxamide, alkylthio or    haloalkylthio; and    wherein at least one of Y or X is N.

DISCLOSURE OF THE INVENTION

The present inventors have energetically investigated to find out suchcompounds that have cysteine protease inhibitory activity and found thatthe oxadiazole derivative of formula (I) of the present inventionaccomplishes the purpose.

The oxadiazole derivative of formula (I) of the present invention is notknown at all as a cysteine protease inhibitor at all.

The present invention relates to

-   (1) an oxadiazole derivative of formula (I),

wherein R is

-   (i) hydrogen,-   (ii) C1–8 alkyl,-   (iii) CycA,-   (iv) C1–8 alkyl substituted with a group selected from halogen atom,    CycA, nitro, CF₃ and cyano,

CycA is a C3–15 mono-, bi- or tri-cyclic carboring or a mono-, bi- ortri-cyclic 3–15 membered heteroring comprising 1–4 of nitrogen, 1–2 ofoxygen and/or 1 of sulfur;

-   R¹⁶ is-   (1) C1–8 alkyl,-   (2) C2–8 alkenyl,-   (3) C2–8 alkynyl,-   (4) CycA or-   (5) C1–8 alkyl, C2–8 alkenyl or C2–8 alkynyl substituted with a    group selected from halogen atom, nitro, CF₃, cyano, CycA, NR¹⁸R¹⁹    and —NHC(O)-CycA;-   R¹⁷, R¹⁸ and R¹⁹ each independently represents hydrogen or C1–4    alkyl,-   AA¹ is-   (i) a single bond, or

wherein R¹ and R² are the same or different to represent

-   (i) hydrogen,-   (ii) C1–8 alkyl,-   (iii) CycA or-   (iv) C1–8 alkyl substituted with 1–5 of group selected from the    following (1) to (8):-   (1) —NR² ¹R² ²,-   (2) —OR² ³,-   (3) —SR² ⁴,-   (4) —COR² ⁵,-   (5) —NR ² ⁶CONR² ¹R² ²,-   (6) guanidino,-   (7) CycA,-   (8) —NR² ⁶SO₂R² ¹; or-   R¹ and R² are taken together to form C2–8 alkylene (wherein one    carbon atom may be replaced by oxygen, sulfur or —NR²⁰— and the    alkylene may be substituted with —NR²¹R²² or —OR²³,-   R²⁰ is hydrogen, C1–4 alkyl, —COO—(C1–4 alkyl), phenyl or C1–4 alkyl    substituted with phenyl,-   R²¹, R²², R²³, R²⁴ and R²⁶ are the same or different to represent    hydrogen, C1–4 alkyl, phenyl or C1–4 alkyl substituted with phenyl,-   R²⁵ is C1–4 alkyl, phenyl, —NR²¹R²², wherein all symbols have the    same meaning as above, —OR²³, wherein R²³ is the same meaning as    above, or C1–4 alkyl substituted with phenyl,-   R³ is hydrogen, C1–8 alkyl, phenyl or C1–8 alkyl substituted with    phenyl or-   R³ is taken together with R1 to form C2–6 alkylene, wherein one    carbon atom may be replaced by oxygen, sulfur or —NR²⁰— and the    alkylene may be substituted with —NR²¹R²² or —OR²³, or when AA¹ is

-   AA¹ and R may be taken together to form

is a 5–12 membered mono- or bi-cyclic heteroring and the other symbolsare the same meanings as above,

-   AA² is-   (i) a single bond,

wherein R⁴ and R⁵ are the same or different to represent

-   (1) hydrogen,-   (2) C1–8 alkyl,-   (3) CycA or-   (4) C1–8 alkyl substituted with 1–5 of group selected from the    following (a) to (h):-   (a) —NR⁴ ¹R⁴ ², (b) —OR⁴ ³, (c) —SR⁴ ⁴, (d) —COR⁴ ⁵, (e) —NR⁴ ⁶CONR⁴    ¹R⁴ ², (f) guanidino, (g) CycA, (h) —NR⁴ ⁶SO₂R⁴ ¹; or R⁴ and R⁵ are    taken together to form C2–8 alkylene, wherein one carbon atom may be    replaced by oxygen, sulfur or —NR⁴⁰— and the alkylene may be    substituted with —NR⁴¹R⁴² or —OR⁴³,-   R⁴⁰ is hydrogen, C1–4 alkyl, —COO—(C1–4 alkyl), phenyl or C1–4 alkyl    substituted with phenyl,-   R⁴¹, R⁴², R⁴³, R⁴⁴ and R⁴⁶ are the same or different to represent    hydrogen, C1–4 alkyl, phenyl or C1–4 alkyl substituted with phenyl,-   R⁴⁵ is C1–4 alkyl, phenyl, —NR⁴¹R⁴², wherein all symbols are the    same meaning as above, —OR⁴³, wherein R⁴³ is the same meaning as    above, or C1–4 alkyl substituted with phenyl,-   R⁶ is hydrogen, C1–8 alkyl, phenyl or C1–8 alkyl substituted with    phenyl or-   R⁶ is taken together with R⁴ to form C2–6 alkylene, wherein one    carbon atom may be replaced by oxygen, sulfur or —NR⁴⁰— and the    alkylene may be substituted with —NR⁴¹R⁴² or —OR⁴³,-   R⁴⁸ is hydrogen, C1–4 alkyl, phenyl or C1–4 alkyl substituted with    phenyl or-   when AA¹ is a single bond, R⁴⁸ and R may be taken together to form    C2–6 alkylene, wherein one carbon atom may be replaced by oxygen,    sulfur or —NR⁴⁷, wherein R⁴⁷ is hydrogen or C1–4 alkyl, CycC is a    3–17 membered mono- or bi-cyclic heteroring, CycD is a C3–14 mono-    or bi-cyclic carboring or a 3–14 membered mono- or bi-cyclic    heteroring, or-   AA² and AA¹ are taken together to form,

wherein CycE is a 4–18 membered mono- or bi-cyclic heteroring, CycF is a5–8 membered monocyclic heteroring, and the other symbols have the samemeanings as above,

-   R⁷ and R⁸ are the same or different to represent-   (i) hydrogen,-   (ii) C1–8 alkyl,-   (iii) CycA or-   (iv) C1–8 alkyl substituted with 1–5 of group selected from the    following (1) to (8);-   (1) —NR⁶¹R⁶², (2) —OR⁶³, (3) —SR⁶⁴, (4) —COR⁶⁵, (5)    —NR⁶⁶CONR⁶¹R⁶², (6) guanidino, (7) CycA, (8) —NR⁶⁶SO₂R⁶¹, or-   R⁷ and R⁸ are taken together to form C2–8 alkylene, wherein one    carbon atom may be replaced by oxygen, sulfur or —NR⁶⁰— and the    alkylene may be substituted with —NR⁶¹R⁶² or —OR⁶³,-   R⁶⁰ is hydrogen, C1–4 alkyl, —COO—(C1–4 alkyl), phenyl or C1–4 alkyl    substituted with phenyl,-   R⁶¹, R⁶², R⁶³, R⁶⁴ and R⁶⁶ are the same or different to represent    hydrogen, C1–4 alkyl, phenyl or C1–4 alkyl substituted with phenyl,    R⁶⁵ is C1–4 alkyl, phenyl, —NR⁶¹R⁶², wherein all symbols are the    same meanings as above, —OR⁶³, wherein R⁶³ is the same meaning as    above, or C1–4 alkyl substituted with phenyl,-   R⁹ is hydrogen, C1–8 alkyl, phenyl or C1–8 alkyl substituted with    phenyl or-   R⁹ is taken together with R⁷ to form C2–6 alkylene, wherein one    carbon atom may be replaced by oxygen, sulfur or —NR⁶⁰— and the    alkylene may be substituted with —NR⁶¹R⁶² or —OR⁶³,

-   R¹⁰ is-   (i) C1–8 alkyl,-   (ii) C2–8 alkenyl,-   (iii) CycA,-   (iv) —COR⁷¹ or-   (v) C1–8 alkyl substituted with 1–3 of group selected from CycA,    guanidino, —COR⁷¹—NR⁷²R⁷³, —OR⁷⁴, cyano or —P(O) (OR⁷⁸)₂,-   wherein R⁷¹ is-   (1) C1–4 alkyl,-   (2) C1–4 alkoxy,-   (3) CycA,-   (4) —O-CycA,-   (5) —NR⁷²R⁷³,-   (6) C1–4 alkyl substituted with CycA,-   (7) C1–4 alkoxy substituted with CycA, or-   (8) hydroxy,-   R⁷² and R⁷³ are the same or different to represent hydrogen, C1–8    alkyl, CycA or C1–8 alkyl substituted with CycA,-   R⁷⁴ is-   (1) hydrogen,-   (2) C1–8 alkyl,-   (3) CycA,-   (4) —SiR⁷⁵R⁷⁶R⁷⁷, wherein R⁷⁵, R⁷⁶ and R⁷⁷ are the same or different    to represent C1–8 alkyl, phenyl or C1–8 alkyl substituted with    phenyl, or-   (5) C1–8 alkyl substituted with CycA,-   R⁷⁸ is C1–8 alkyl, phenyl, or C1–8 alkyl substituted with phenyl;    and, CycA's included in R, R¹, R², R⁴, R⁵, R⁷, R⁸ and R¹⁶ are the    same or different, and CycA, CycB, CycC, CycD, CycE and CycF,    independently, may be substituted with 1–5 of R²⁷:-   R²⁷ is-   (1) C1–8 alkyl,-   (2) halogen atom,-   (3) —NR¹¹R¹²,-   (4) —OR¹³,-   (5) a C5–10 mono-or bi-cyclic carboring,-   (6) nitro,-   (7) CF₃,-   (8) cyano,-   (9) a 5–10 membered mono- or bi-cyclic heteroring-   (10) —SR¹⁴,-   (11) —COR¹⁵,-   (12) oxo,-   (13) —SO₂R¹⁵,-   (14) —OCF₃ or-   (15) C1–8 alkyl substituted with 1–5 of group selected from the    following (a) to (m):-   (a) halogen atom, (b) —NR¹¹R¹², (c) —OR¹³, (d) a C5–10 mono- or    bi-cyclic carboring, (e) nitro, (f) CF₃, (g) cyano, (h) a 5–10    membered mono- or bi-cyclic heteroring, (j) —SR¹⁴, (k) —COR¹⁵, (l)    —SO₂R¹⁵, (m) —OCF₃,    wherein R¹¹ and R¹² are the same or different to represent hydrogen,    C1–4 alkyl, —COO—(C1–4 alkyl), phenyl or C1–4 alkyl substituted with    phenyl,-   R¹³ and R¹⁴ are the same or different to represent hydrogen, C1–4    alkyl, phenyl or C1–4 alkyl substituted with phenyl,-   R¹⁵ is C1–4 alkyl, phenyl, —NR¹¹R¹², wherein all symbols have the    same meanings as above, —OR¹³, wherein R¹³ is the same meaning as    above, or C1–4 alkyl substituted with phenyl,    or a non-toxic salt thereof,-   (2) a method for the preparation thereof and-   (3) a pharmaceutical agent comprising the oxadiazole derivative and    non-toxic salt thereof as active ingredient.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

In the compound of formula (I), in

which AA¹ and R together form,

is a 5–12 membered heteroring containing 1–3 of nitrogen, 1 of oxygen,and/or 1 of sulfur (this heteroring may be substituted with 1–5 of R²⁷).

And to describe

concretely, it is

wherein J¹ is oxygen, sulfur, —NR²⁹—, wherein R²⁹ is hydrogen, C1–4alkyl, CycA or C1–4 alkyl substituted with CycA, C1–3 alkylene or C2–3alkenylene,

-   J² is a single bond or C1–2 alkylene,-   Y² is —N═CH—, —CH═N— or C1–2 alkylene,-   J³ is carbonyl or C1–3 alkylene,-   Y³ is C1–3 alkylene, oxygen or —NR²⁹—, wherein R²⁹ is the same    meaning as above,-   R²⁸ is hydrogen, C1–4 alkyl, CycA or C1–4 alkyl substituted with    CycA, or-   R²⁸ is taken together with R¹ to form C2–4 alkylene, and the other    symbols have the same meaning as above and each ring may be    substituted with 1–5 of R²⁷.

In the compound of formula (I), in

which AA² represents, CycC is a 3–17 membered heteroring which contains1–2 of nitrogen, 1 of oxygen and/or 1 of sulfur (this ring may besubstituted with 1–5 of R²⁷).

And to describe

concretely,

wherein J⁴, Y⁴ and L⁴ are the same or different to represent a singlebond or C1–3 alkylene, wherein J⁴, Y⁴ and L⁴ do not represent a singlebond at the same time,

-   J⁵ is C1–6 alkylene,-   Y⁵ is a single bond, C1–3 alkylene or —NR⁶⁷—, wherein R⁶⁷ is    hydrogen, C1–4 alkyl, phenyl or C1–4 alkyl substituted with phenyl,-   J⁸ is C1–5 alkylene, wherein one carbon atom may be replaced by    oxygen,-   Y⁸ is a single bond or C1–4 alkylene,-   L⁸ is —N— or —CH—,    and the other symbols have the same meaning as above and each ring    may be substituted with 1–5 of R²⁷.

And in

which AA² represents, CycD is a C3–14 mono- or bi-cyclic carboring or3–14 membered heteroring which contains 1–2 of nitrogen, 1 of oxygenand/or 1 of sulfur (this carboring and heteroring may be substitutedwith 1–5 of R²⁷).

And to describe

concretely, it is

wherein J⁶ and Y⁶ are the same or different to represent a single bondor C1–3 alkylene, wherein J⁶ and Y⁶ do not represent a single bond atthe same time,

-   J⁷ is C1–6 alkylene, wherein one carbon atom may be replaced by    oxygen, sulfur or —NR⁶⁷—, wherein R⁶⁷ has the same meaning as above,-   J⁹ is C1–3 alkylene, oxygen, sulfur or —NR⁶⁷—, wherein R⁶⁷ is the    same meaning as above,    and the other symbols have the same meanings as above and each ring    may be replaced by 1–5 of R²⁷.

In the compounds of the formula (I), in

which AA¹ and AA² together form,CycE is a 4–18 membered heteroring which contains 1–2 of nitrogen, 1 ofoxygen and/or 1 of —S(O)_(p)— (this heteroring may be substituted with1–5 of R²⁷).

And to describe

concretely, it is

wherein

is a single bond or a double-bond,

-   J¹⁰ and Y¹⁰ are the same or different to represent a single bond or    C1–3 alkylene,-   L¹⁰ is a single bond, C1–3 alkylene, —NR⁵⁷—, wherein R⁵⁷ is    hydrogen, C1–4 alkyl, phenyl or C1–4 alkyl substituted with phenyl,    —N═, oxygen or —S(O)_(p)—, wherein p is 0 or an integer of 1 to 2,-   J¹² and Y¹² are the same or different to represent a single bond or    C1–3 alkylene,-   L¹² is C1–3 alkylene, —NR⁵⁷—, wherein R⁵⁷ is the same meaning as    above), —N═, ═N—, oxygen or —S(O)_(p)—, wherein p has the same    meaning as above,    and the other symbols have the same meanings as above and each ring    may be substituted with 1–5 of R²⁷.

And in

which AA¹ and AA² together form,CycF is a 5–8 membered heteroring containing 2 of nitrogen.

And to describe

concretely, it is

wherein J¹¹ is carbonyl or C2–4 alkylene and the other symbols have thesame meaning as above and the ring therein may be substituted with 1–5of R²⁷.

In the present specification, C1–4 alkyl is methyl, ethyl, propyl, butyland isomers thereof.

In the present specification, C1–8 alkyl is methyl, ethyl, propyl,butyl, pentyl, hexyl, heptyl, octyl and isomers thereof.

In the present specification, C2–8 alkenyl is, ethyl, propyl, butyl,pentyl, hexyl, heptyl, octyl containing 1–3 of double bond and isomersthereof. For example, vinyl, propenyl, butenyl, hexenyl, hexadienyl,octadienyl, etc. are included.

In the present specification, C2–8 alkynyl is ethyl, propyl, butyl,pentyl, hexyl, heptyl, octyl containing 1–3 of triple bond and isomersthereof. For example, ethynyl, propynyl, butynyl, pentynyl, hexynyl,heptynyl, octynyl, etc. are included.

In the present specification, C1–4 alkyl substituted with phenyl isphenylmethyl, phenylethyl, phenylpropyl, phenylbutyl and isomersthereof.

In the present specification, C1–2 alkylene is, methylene, ethylene andisomers thereof.

In the present specification, C1–3 alkylene is, methylene, ethylene,trimethylene and isomers thereof.

In the present specification, C1–4 alkylene is methylene, ethylene,trimethylene, tetramethylene and isomers thereof.

In the present specification, C1–5 alkylene is methylene, ethylene,trimethylene, tetramethylene, pentamethylene and isomers thereof

In the present specification, C1–6 alkylene is methylene, ethylene,trimethylene, tetramethylene, pentamethylene, hexamethylene and isomersthereof.

In the present specification, C2–4 alkylene is ethylene, trimethylene,tetramethylene and isomers thereof.

In the present specification, C2–6 alkylene is ethylene, trimethylene,tetramethylene, pentamethylene, hexamethylene and isomers thereof.

In the present specification, C2–8 alkylene is ethylene, trimethylene,tetramethylene, pentamethylene, hexamethylene, heptamethylene,octamethylene and isomers thereof.

In the present specification, C2–6 alkylene whose one carbon atom may bereplaced by oxygen, sulfur, —NR²⁰—, —NR⁴⁰— or —NR⁶⁰— is ethylene,trimethylene, tetramethylene, pentamethylene, hexamethylene and isomersthereof, wherein one carbon atom thereof may be replaced by oxygen,sulfur, —NR²⁰—, —NR⁴⁰—, or —NR⁶⁰—, for example, such groups are—CH₂—O—CH₂—, —CH₂—CH₂—O—CH₂—, —CH₂—CH₂—S—CH₂—, —CH₂—CH₂—NH—CH₂—,—CH₂—CH₂—O—CH₂—CH₂—, —CH₂—CH₂—S—CH₂—CH₂—, —CH₂—CH₂—NH—CH₂—CH₂—,—CH₂—CH₂—N(CH₃) —CH₂—CH₂—, etc.

In the present specification, C2–8 alkylene whose one carbon atom may bereplaced by oxygen, sulfur, —NR²⁰—, —NR⁴⁰— or —NR⁶⁰— is ethylene,trimethylene, tetramethylene, pentamethylene, hexamethylene,heptamethylene, octamethylene and isomers thereof, wherein one carbonatom may be replaced by oxygen, sulfur, —NR²⁰—, —NR⁴⁰— or —NR⁶⁰—, forexample, such groups are —CH₂—O—CH₂—, —CH₂—CH₂—O—CH₂—, —CH₂—CH₂—S—CH₂—,—CH₂—CH₂—NH—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—, —CH₂—CH₂—S—CH₂—CH₂—,—CH₂—CH₂—NH—CH₂—CH₂—, —CH₂—CH₂—N(CH₃)—CH₂—CH₂—, etc.

In the present specification, C2–3 alkenylene means vinylene andallylene and isomers thereof.

In the present specification, halogen atom means chlorine, fluorine,bromine and iodine atom.

In the present specification, mono- or bi-cyclic C5–10 carboring ismono- or bi-cyclic C5–10 carboaryl or partially or completely saturatedone thereof. For example, cyclopentane, cyclohexane, cycloheptane,cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, benzene,pentalene, indene, naphthalene, azulene, perhydropentalene,perhydroindene, perhydronaphthalene, perhydroazulene, adamantyl ring,etc. are included.

In the present specification, mono-, bi- or tri-cyclic C3–15 carboringis mono-, bi- or tri-cyclic carboaryl or partially or completelysaturated one thereof. For example, cyclopropane, cyclobutane,cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene,cyclopentadiene, cyclohexadiene, benzene, pentalene, indene,naphthalene, azulene, fluorene, phenanthrene, anthracene,acenaphthylene, biphenylene, perhydropentalene, perhydroindene,perhydronaphthalene, perhydroazulene, perhydrofluorene,perhydrophenanthrene, perhydroanthracene, perhydroacenaphthylene,perhydrobiphenylene, adamantyl ring etc. are included.

In the present specification, mono- or bi-cyclic 5–10 memberedheteroring containing 1–4 of nitrogen, 1 of oxygen and/or sulfur ismono- or bi-cyclic 5–10 membered heteroaryl containing 1–4 of nitrogen,1 of oxygen and/or sulfur or partially or completely saturated onethereof.

Above 5–10 membered mono- or bi-cyclic heteroaryl containing 1–4 ofnitrogen, 1 of oxygen and/or 1 of sulfur is, for example, pyrrole,imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, azepine, diazepine, furan, pyrane, oxepine,thiophene, thiaine (thiopyrane), thiepine, oxazole, isooxazole,thiazole, isothiazole, oxadiazole, oxazine, oxadiazine, oxazepine,oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,thiadiazepine, indole, isoindole, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline,phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,benzoxazole, benzothiazole, benzoimidazole, etc.

Above partially or completely saturated mono- or bi-cyclic 5–10 memberedheteroaryl containing 1–4 of nitrogen, 1 of oxygen and/or 1 of sulfuris, for example, pyrroline, pyrrolidine, imidazoline, imidazolidine,triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline,pyrazolidine, piperidine, piperazine, tetrahydropyridine,tetrahydropyrimidine, tetrahydropyridazine, dihydrofuran,tetrahydrofuran, dihydropyrane, tetrahydropyrane, dihydrothiophene,tetrahydrothiophene, dihydrothiaine (dihydrothiopyrane),tetrahydrothiaine (tetrahydrothiopyrane), oxazoline (dihydrooxazole),oxazolidine (tetrahydroxazole), dihydroisoxazole, tetrahydroisoxazole,oxadiazoline (dihydroxadiazole), oxadiazolidine (tetrahydroxadiazole),thiazoline (dihydrothiazole), thiazolidine (tetrahydrothiazole),dihydroisothiazole, tetrahydroisothiazole, morpholine, thiomorpholine,indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran,dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene,perhydrobenzothiophene, dihydroisobenzothiophene,perhydroisobenzothiophene, dihydroindazole, perhydroindazole,dihydroquinoline, tetrahydroquinoline, perhydroquinoline,dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline,dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine,dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine,dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline,dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline,dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline,dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole,perhydrobenzothiazole, dihydrobenzoimidazole, perhydrobenzoimidazole,etc.

In the present specification, a 3–15 membered mono-, bi- or tri-cyclicheteroring containing 1–4 of nitrogen, 1–2 of oxygen and/or 1 of sulfuris 3–15 membered mono-, bi- or tri-cyclic heteroaryl containing 1–4 ofnitrogen, 1–2 of oxygen and/or 1 of sulfur or partially or completelysaturated one thereof.

Above 3–15 membered mono-, bi- or tri-cyclic heteroring containing 1–4of nitrogen, 1–2 of oxygen and/or 1 of sulfur is, for example, pyrrole,imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, azepine, diazepine, furan, pyrane, oxepine,oxazepine, thiophene, thiaine (thiopyrane), thiepine, oxazole,isoxazole, thiazole, isothiazole, oxadiazole, oxazine, oxadiazine,oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,thiadiazepine, indole, isoindole, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline,phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,benzoxazole, benzoxadiazole, benzothiazole, benzoimidazole, carbazole,acridine ring, etc.

Above partially or completely saturated mono-, bi- or tri-cyclic 3–15membered heteroring containing 1–4 of nitrogen, 1–2 of oxygen and/or 1of sulfur is, aziridine, oxirane, azetidine, oxetane, thiirane,thietane, pyrroline, pyrrolidine, imidazoline, imidazolidine,triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline,pyrazolidine, piperidine, piperazine, tetrahydropyridine,tetrahydropyrimidine, tetrahydropyridazine, dihydrofuran,tetrahydrofuran, dihydropyrane, tetrahydropyrane, dihydrothiophene,tetrahydrothiophene, dihydrothiaine (dihydrothiopyrane),tetrahydrothiaine (tetrahydrothiopyrane), oxazoline (dihydroxazole),oxazolidine (tetrahydroxazole), dihydroisoxazole, tetrahydroisoxazole,oxadiazoline (dihydroxadiazole), oxadiazolidine (tetrahydroxadiazole),thiazoline (dihydrothiazole), thiazolidine (tetrahydrothiazole),dihydroisothiazole, tetrahydroisothiazole, morpholine, thiomorpholine,indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran,dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene,perhydrobenzothiophene, dihydroisobenzothiophene,perhydroisobenzothiophene, dihydroindazole, perhydroindazole,dihydroquinoline, tetrahydroquinoline, perhydroquinoline,dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline,dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine,dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine,dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline,dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline,dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline,dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole,perhydrobenzothiazole, dihydrobenzoimidazole, perhydrobenzoimidazole,benzoxazepine, benzoxadiazepine, benzothiazepine, benzothiadiazepine,benzazepine, benzodiazepine, indoloxazepine, indolotetrahydroxazepine,indoloxadiazepine, indolotetrahydroxadiazepine, indolothiazepine,indolotetrahydrothiazepine, indolothiadiazepine,indolotetrahydrothiadiazepine, indolazepine, indolotetrahydroazepine,indolodiazepine, indolotetrahydrodiazepine, benzofurazane,benzothiadiazole, benzotriazole, camphor, imidazothiazole,dihydrocarbazole, tetrahydrocarbazole, perhydrocarbazole,dihydroacridine, tetrahydroacridine, perhydroacridine, dioxolane,dioxane, dioxazine ring etc.

In the present specification, a 5–12 membered heteroring containing 1–3of nitrogen, 1 of oxygen and/or 1 of sulfur atom, i.e.

is, for example, a ring represented by

Specifically, 2-oxo-1,3,4-triazoline, 5-oxo-1,2,4-oxadiazoline,5-oxo-1,2,4-thiadiazoline, 4-oxoimidazoline,3,4-dihydro-4-oxopyrimidine, 3,4,5,6-tetrahydro-4-oxopyrimidine,2-oxoindoline, 2-oxo-tetrahydroquinoline, 1,2-dihydro-2-oxoquinazoline,1,2-dihydro-2-oxoquinoxaline, 3-oxopyrazolidine,perhydro-3-oxopyridazine, 2-oxo-1,3,4-oxadiazolidine,perhydro-2-oxo-1,3,4-oxadiazine, etc. are included.

In the specification, 3–17 membered heteroring containing 1–2 ofnitrogen, 1 of oxygen and/or 1 of sulfur represented by CycC is, forexample, a ring represented by

Specifically, pyrrolidine, imidazolidine, pyrazolidine, piperidine,piperazine, perhydropyrimidine, perhydropyridazine, thiazolidine,indoline, isoindoline, tetrahydroquinoline, tetrahydroisoquinoline, etc.are included.

In the specification, a C3–14 mono- or bi-cyclic carboring or 3–14membered heteroring containing 1–2 of nitrogen, 1 of oxygen, and/or 1 ofsulfur represented by CycD is, for example, a ring represented by

Specifically, cyclopentane, cyclohexane, cycloheptane, benzene, indan,tetrahydronaphthalene, oxorane, oxane, thiorane, thian, pyrrolidine,piperidine, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane,7-azabicyclo[2.2.1]heptane, 7-oxobicyclo[2.2.1]heptane,7-thiabicyclo[2.2.1]heptane, etc. are included.

In the specification, 4–18 membered heteroring containing 1–2 ofnitrogen, 1 of oxygen and/or 1 of —S(O)_(p)—, i.e. CycE is, for example,a ring represented by

Specifically, 2-oxopyrrolidine, 2-oxopiperidine, 2-oxoperhydroazepine,2-oxopiperazine, 3-oxomorpholine, 1,1,-dioxo-3-isothiazolidine,1,1-dioxo-3-isothiazine, 4-oxodiazepine, 2-oxoindoline,2-oxo-tetrahydroquinoline, 1,1-dioxo-3-benzisothiazolidine,1,1-dioxo-3-benzisothiazine, etc. are included.

In the present invention, 5–8 membered heteroring which contains 2 ofnitrogen. i.e. CycF is, for example, a ring represented by

Specifically, 2,4-dioxoimidazolidine, 2-oxopiperazine,2-oxoperhydrodiazepine substituted by R¹ and R² are included.

In the present invention, as may be easily understood by those skilledin the art, the symbol:

indicates that the substituent attached thereto is in front of the sheet(β-position) unless specified,

indicates that the substituent attached thereto is behind the sheet(α-position) unless specified, and

indicates that the substituent attached thereto is in β-position orα-position or a mixture thereof.

In the formula (I), all groups represented by R are preferable, butpreferably, R is

-   (i) hydrogen,-   (ii) C1–8 alkyl,-   (iii) CycA,-   (iv) C1–8 alkyl substituted with a group selected from CycA and    nitro,

more preferably, C1–8 alkyl or C1–8 alkyl substituted with CycA ornitro.

Any group represented by R¹⁶ is preferable, but more preferably, R¹⁶ is

-   [I] (1) C1–8 alkyl,-   (2) C2–8 alkenyl,-   (3) C2–8 alkynyl,-   (4) CycA, or-   (5) C1–8 alkyl substituted with a group selected from CycA or    —NHC(O)-CycA,-   (6) C2–8 alkenyl substituted with CycA or-   (7) C2–8 alkynyl substituted with CycA,    wherein CycA may be substituted with 1–5 of R^(27a), and-   R^(27a) is (1) C1–8 alkyl,-   (2) halogen,-   (3) —NR¹¹R¹²,-   (4) —OR¹³,-   (5) phenyl,-   (6) nitro,-   (7) CF₃,-   (8) cyano,-   (9) tetrazole,-   (10) —SR¹⁴,-   (11) —COR¹⁵,-   (12) oxo or-   (13) C1–8 alkyl substituted with 1–5 of group selected from the    following (a) to (k):-   (a) halogen, (b) —NR¹¹R¹², (c) —OR¹³, (d) phenyl, (e) nitro, (f)    CF₃, (g) cyano, (h) tetrazole, (j) —SR¹⁴, (k) —COR¹⁵, or-   [II] (a) C1–8 alkyl, C2–8 alkenyl or C2–8 alkynyl substituted with a    group selected from halogen, CF₃, nitro, cyano or NR¹⁸R¹⁹ or-   (b) (1) CycA containing 1–5 of substituent R²⁷ or-   (2) C1–8 alkyl, C2–8 alkenyl or C2–8 alkynyl substituted with CycA,    which contains 1–5 of substituent R²⁷,    wherein at least one of R27 described in (1) and (2) is selected    from-   (i) a C5–10 mono- or bi-cyclic carboring,-   (ii) a 5–10 membered mono- or bi-cyclic heteroring,-   (iii) —SO₂R¹⁵, (iv) —OCF₃ or-   (v) C1–8 alkyl substituted with 1–5 of the group selected from (a)    halogen, (b) —NR¹¹R¹², (c) —OR¹³, (d) a C5–10 mono-or bi-cyclic    carboring, (e) nitro, (f) CF₃, (g) cyano, (h) a 5–10 membered mono-    or bi-cyclic heteroring, (j) —SR¹⁴, (k) —COR¹⁵, (1) —SO₂R¹⁵ and (m)    —OCF₃ (at least one is a C5–10 mono-or bi-cyclic carboring, a 5–10    mono- or bi-cyclic heteroring, —SO₂R¹⁵ or —OCF₃))

Particularly preferably,

-   [I] (1) C1–8 alkyl,-   (2) C2–8 alkenyl,-   (3) C2–8 alkynyl,-   (4) CycA or-   (5) C1–8 alkyl substituted with a group selected from CycA or    —NHC(O)-CycA,-   (6) C2–8 alkenyl substituted with CycA or-   (7) C2–8 alkynyl substituted with CycA,    wherein CycA is a mono- or bi-cyclic C5–10 carboaryl which may be    substituted with 1–5 of R²⁷ or partially or completely saturated one    thereof, or mono- or bi-cyclic 5–10 membered heteroaryl containing    1–2 of nitrogen, 1–2 of oxygen and/or 1 of sulfur atom, or partially    or completely saturated one thereof or-   [II] (a) C1–8 alkyl, C2–8 alkenyl or C2–8 alkynyl substituted with a    group selected from halogen atom, CF₃, nitro, cyano and NR¹⁸R¹⁹, or-   (b) CycA containing 1–5 of substituent R²⁷ or-   (2) C1–8 alkyl, C2–8 alkenyl or C2–8 alkynyl substituted with CycA,    which contains 1–5 of substituent R²⁷,    wherein at least one of R²⁷ described in (1) and (2) is selected    from-   (i) a C5–10 mono- or bi-cyclic carboring,-   (ii) a 5–10 membered mono- or bi-cyclic heteroring,-   (iii) —SO₂R¹⁵, (iv) —OCF₃ or-   (v) C1–8 alkyl substituted with 1–5 of group selected from (a)    halogen, (b) —NR¹¹R², (c) —OR¹³, (d) a C5–10 mono- or bi-cyclic    carboring, (e) nitro, (f) CF₃, (g) cyano, (h) a 5–10 membered mono-    or bi-cyclic heteroring, (j) —SR¹⁴, (k) —COR¹⁵, (1) —SO₂R¹⁵ and (m)    OCF₃, wherein at least one group is selected from a C5–10 mono- or    bi-cyclic carboring or a 5–10 membered mono- or bi-cyclic    heteroring, —SO₂R¹⁵ or OCF₃,    above CycA is C5–10 mono- or bi-cyclic carboaryl or partially or    completely saturated one, or 5–10 membered mono- or bi-cyclic    heteroaryl containing 1–2 of nitrogen, 1–2 of oxygen and/or 1 of    sulfur, or partially or completely saturated one thereof.

Particularly preferably, [I] (1) C1–4 alkyl, (2) C2–4 alkenyl, (3) C2–4alkynyl, (4) CycA or (5) C1–4 alkyl, C2–4 alkenyl or C2–4 alkynylsubstituted with CycA which is preferably cyclopentane, cyclohexane,benzene, naphthalene, pyrrolidine, piperidine, piperazine, morpholine,pyrrole, furan, thiophene, pyridine, pyrimidine, pyrazine, pyridazine,indole, isoindole, quinoline, isoquinoline, quinazoline, quinoxaline,phthalazine, benzothiophene, benzofuran, benzoxazole,tetrahydroquinoline, tetrahydroquinazoline, tetrahydroquinoxaline,optionally substituted with 1–5 of R^(27a) or

-   [II] (a) C1–8 alkyl, C2–8 alkenyl or C2–8 alkynyl substituted with a    group selected from halogen, CF₃, nitro, cyano or NR¹⁸R¹⁹ or-   (b) (1) CycA which contains 1–5 of substituent R²⁷, or-   (2) C1–8 alkyl, C2–8 alkenyl or C2–8 alkynyl substituted with CycA    which contains 1–5 of substituent R²⁷,    wherein at least one of R²⁷ described in (1) and (2) is selected    from-   (i) a C5–10 mono- or bi-cyclic carboring,-   (ii) a 5–10 membered mono- or bi-cyclic heteroring,-   (iii) —SO₂R¹⁵, (iv) —OCF₁₃, or-   (v) C1–8 alkyl substituted with 1–5 of group selected from (a)    halogen atom, (b) —NR¹¹R¹², (c) —OR¹³, (d) a C5–1 mono- or bi-cyclic    carboring, (e) nitro, (f) CF₃, (g) cyano, (h) a 5–10 membered mono-    or bi-cyclic heteroring, (j) —SR¹⁴, (k) —COR¹⁵, (1) —SO₂R¹⁵ or (m)    —OCF₃, wherein at least one group is selected from a C5–10 mono- or    bi-cyclic carboring, a 5–10 membered mono- or bi-cyclic heteroring,    —SO₂R¹⁵ or —OCF₃, and    CycA is preferably cyclopentane, cyclohexane, benzene, naphthalene,    pyrrolidine, piperidine, piperazine, morpholine, pyrrole, furan,    thiophene, pyridine, pyrimidine, pyrazine, pyridazine, indole,    isoindole, quinoline, isoquinoline, quinazoline, quinoxaline,    phthalazine, benzothiophene, benzofuran, benzoxadiazole,    tetrahydroquinoline, tetrahydroquinazoline, or    tetrahydroquinoxaline.

In the formula (I), AA¹ is preferably a single bond,

which is formed with R, but more preferably, AA¹ is a single bond or

Any group represented by R¹ is preferable, but more preferably, R¹ ishydrogen, C1–8 alkyl, phenyl or C1–8 alkyl substituted with NH₂, C1–4alkoxy, SH, SCH₃, phenyl, hydroxyphenyl, COOH, CONH₂, guanidino,imidazole or indole. Particularly preferably, R¹ is hydrogen, C1–8alkyl, phenyl or C1–8 alkyl substituted with C1–4 alkoxy or phenyl.Then, any group represented by R² is preferable, but hydrogen isparticularly preferable.

And C3–6 alkylene which R¹ and R² together form is also preferable.

Any group represented by R³ is preferable, but more preferably R³ ishydrogen or C1–4 alkyl.

And C2–4 alkylene which R³ and R¹ together form is also preferable.

In the formula (I), AA² is all preferable, but more preferably, AA² is asingle bond,

Particularly preferably, AA² is a single bond,

Any group represented by R⁴ is preferable, but more preferably, R⁴ ishydrogen, C1–8 alkyl, phenyl or C1–8 alkyl substituted with NH₂, C1–4alkoxy, SH, SCH₃, phenyl, hydroxyphenyl, COOH, CONH₂, guanidino,imidazole or indole. Particularly preferably, R⁴ is hydrogen, C1–8alkyl, phenyl or C1–8 alkyl substituted with C1–4 alkoxy or phenyl.Then, any group represented by R⁵ is preferable, and hydrogen isparticularly preferable.

And C3–6 alkylene which R⁴ and R⁵ together form is also preferable.

Any group represented by R⁶ is preferable, but more preferably R⁶ ishydrogen or C1–4 alkyl.

And C2–4 alkylene which R⁶ and R⁴ together form is also preferable.

R⁴⁸ is all preferable, but more preferably, R⁴⁸ is

-   [I] hydrogen, C1–4 alkyl, phenyl or C1–4 alkyl substituted with    phenyl, or-   [II] C2–6 alkylene, wherein one carbon atom may be replaced by    oxygen, sulfur or —NR⁴⁷—, wherein R⁴⁷ is hydrogen or C1–4 alkyl to    be formed together with R⁴, when AA¹ is a single bond. Particularly    preferably, R⁴⁸ is [I] hydrogen atom or C1–4 alkyl, or-   [II] when AA¹ is a single bond, taken together with R to form    tetramethylene, pentamethylene, —CH₂—CH₂—O—CH₂—CH₂—,    —CH₂—CH₂—NH—CH₂—CH₂— or —CH₂—CH₂—N(CH₃) —CH₂—CH₂—.

In the formula (I), all the groups which AA¹ and AA² together form arepreferable, but preferably, it is

particularly preferably, it is

Any group represented by R⁷ is preferable. More preferably, R⁷ ishydrogen atom, C1–8 alkyl, phenyl, or C1–8 alkyl substituted with NH₂,C1–4 alkoxy, SH, SCH₃, phenyl, hydroxyphenyl, COOH, CONH₂, guanidino,imidazole or indole.

Particularly preferably, R⁷ is hydrogen, C1–8 alkyl, phenyl, or C1–8alkyl substituted with C1–4 alkoxy or phenyl. Then, any grouprepresented by R⁸ is preferable, but hydrogen is most preferable.

And C3–6 alkylene which R⁷ and R⁸ together form is also preferable.

Any group represented by R⁹ is preferable, but more preferably R⁹ ishydrogen or C1–4 alkyl.

And C2–4 alkylene which R⁹ and R⁷ together form is also preferable.

Any group represented by R¹⁰ is preferable, but more preferably R¹⁰ isC1–6 alkyl, CycA or C1–6 alkyl substituted with COR⁷¹, NR⁷²R⁷³, hydroxy,OR⁷⁴ or CycA, more preferably C1–4 alkyl, or C1–4 alkyl substituted withphenyl, NR⁷²R⁷³ or C3–6 cycloalkyl.

In the present invention, preferable compounds are the compound offormula (Ia-1)

wherein all symbols have the same meanings as above, the compound offormula (Ib-1)

wherein all symbols have the same meanings as above, the compound offormula (Ic-1)

wherein all symbols have the same meanings as above), the compound offormula (Id-1)

wherein all symbols have the same meanings as above), the compound offormula (Ie-1)

wherein all symbols have the same meanings as above), the compound offormula (If-1)

wherein all symbols have the same meanings as above, the compound offormula (Ig-1)

wherein all symbols have the same meanings as above, the compound offormula (Ih-1)

wherein all symbols have the same meanings as above, the compound offormula (Ii-1)

wherein all symbols have the same meanings as above, the compound offormula (Ij-1)

wherein all symbols have the same meanings as above, the compound offormula (Ik-1)

wherein all symbols have the same meanings as above, the compound offormula (Im-1)

wherein all symbols have the same meanings as above, the compound offormula (In-1)

wherein all symbols have the same meanings as above, the compound offormula (Ia-2)

wherein all symbols have the same meanings as above, the compound offormula (Ib-2)

wherein all symbols have the same meanings as above, the compound offormula (Ic-2)

wherein all symbols have the same meanings as above, the compound offormula (Id-2)

wherein all symbols have the same meanings as above, the compound offormula (Ie-2)

wherein all symbols have the same meanings as above, the compound offormula (If-2)

wherein all symbols have the same meanings as above, the compound offormula (Ig-2)

wherein all symbols have the same meanings as above, the compound offormula (Ih-2)

wherein all symbols have the same meanings as above, the compound offormula (Ii-2)

wherein all symbols have the same meanings as above, the compound offormula (Ij-2)

wherein all symbols have the same meanings as above, the compound offormula (Ik-2)

wherein all symbols have the same meanings as above, the compound offormula (Im-2)

wherein all symbols have the same meanings as above, the compound offormula (In-2)

wherein all symbols have the same meanings as above, the compound offormula (Ia-3)

wherein all symbols have the same meanings as above, the compound offormula (Ib-3)

wherein all symbols have the same meanings as above, the compound offormula (Ic-3)

wherein all symbols have the same meanings as above, the compound offormula (Id-3)

wherein all symbols have the same meanings as above, the compound offormula (Ie-3)

wherein all symbols have the same meanings as above, the compound offormula (If-3)

wherein all symbols have the same meanings as above, the compound offormula (Ig-3)

wherein all symbols have the same meanings as above, the compound offormula (Ih-3)

wherein all symbols have the same meanings as above, the compound offormula (Ii-3)

wherein all symbols have the same meanings as above, the compound offormula (Ij-3)

wherein all symbols have the same meanings as above, the compound offormula (Ik-3)

wherein all symbols have the same meanings as above, the compound offormula (Im-3)

wherein all symbols have the same meanings as above, the compound offormula (In-3)

wherein all symbols have the same meanings as above, the non-toxic saltthereof.

Concretely, the compounds described in the following Examples and tables1 to 36 are preferable.

In the tables below, the numbers in front of the group means theposition of substituent, and Ph means phenyl.

TABLE 1 (I-1A)

No. R²⁷ 1 2-F 2 3-F 3 4-F 4 2-CN 5 3-CN 6 4-CN 7 3-NO₂ 8 4-NO₂ 9 3-CH₃10 4-CH₃ 11 2-CH₂—Cl 12 4-CH₂—Cl 13 4-Cl 14 4-CF₃ 15 4-CH₂CH₃ 164-(CH₂)₃CH₃ 17 4-C(CH₃)₃ 18 4-N(CH₃)₂ 19 4-OCH₃ 20 4-OCH₂CH₃ 21 4-Ph 222,3-di-CH₃ 23 3,5-di-F 24 3,4-di-F

TABLE 2 (I-2A)

No. R¹⁶ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 3 (I-3A)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

TABLE 4 (I-4A)

No. R⁷ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 5 (I-5A)

No. R¹⁰ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

TABLE 6 (I-6A)

No. R¹⁰ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

TABLE 7 (I-1B)

No. R²⁷ 1 2-F 2 3-F 3 4-F 4 2-CN 5 3-CN 6 4-CN 7 3-NO₂ 8 4-NO₂ 9 3-CH₃10 4-CH₃ 11 2-CH₂—Cl 12 4-CH₂—Cl 13 4-Cl 14 4-CF₃ 15 4-CH₂CH₃ 164-(CH₂)₃CH₃ 17 4-C(CH₃)₃ 18 4-N(CH₃)₂ 19 4-OCH₃ 20 4-OCH₂CH₃ 21 4-Ph 222,3-di-CH₃ 23 3,5-di-F 24 3,4-di-F

TABLE 8 (I-2B)

No. R¹⁶ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 9 (I-3B)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

TABLE 10 (I-4B)

No. R⁷ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 11 (I-5B)

No. R¹⁰ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

TABLE 12 (I-6B)

No. R¹⁰ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

TABLE 13 (I-7A)

No. R²⁷ 1 2-F 2 3-F 3 4-F 4 2-CN 5 3-CN 6 4-CN 7 3-NO₂ 8 4-NO₂ 9 3-CH₃10 4-CH₃ 11 2-CH₂—Cl 12 4-CH₂—Cl 13 4-Cl 14 4-CF₃ 15 4-CH₂CH₃ 164-(CH₂)₃CH₃ 17 4-C(CH₃)₃ 18 4-N(CH₃)₂ 19 4-OCH₃ 20 4-OCH₂CH₃ 21 4-Ph 222,3-di-CH₃ 23 3,5-di-F 24 3,4-di-F

TABLE 14 (I-8A)

No. R¹⁶ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 15 (I-9A)

No. R⁷ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 16 (I-10A)

No. R¹⁰ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

TABLE 17 (I-7B)

No. R²⁷ 1 2-F 2 3-F 3 4-F 4 2-CN 5 3-CN 6 4-CN 7 3-NO₂ 8 4-NO₂ 9 3-CH₃10 4-CH₃ 11 2-CH₂—Cl 12 4-CH₂—Cl 13 4-Cl 14 4-CF₃ 15 4-CH₂CH₃ 164-(CH₂)₃CH₃ 17 4-C(CH₃)₃ 18 4-N(CH₃)₂ 19 4-OCH₃ 20 4-OCH₂CH₃ 21 4-Ph 222,3-di-CH₃ 23 3,5-di-F 24 3,4-di-F

TABLE 18 (I-8B)

No. R¹⁶ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 19 (I-9B)

No. R⁷ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 20 (I-10B)

No. R¹⁰ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

TABLE 21 (I-11A)

No. R²⁷ 1 2-CH₂N(CH₃)₂ 2 3-CH₂N(CH₃)₂ 3 4-CH₂N(CH₃)₂ 4

5

6

7

8

9

TABLE 22 (I-11B)

No. R²⁷ 1 2-CH₂N(CH₃)₂ 2 3-CH₂N(CH₃)₂ 3 4-CH₂N(CH₃)₂ 4

5

6

7

8

9

TABLE 23 (I-1C)

No. R²⁷ 1 2-F 2 3-F 3 4-F 4 2-CN 5 3-CN 6 4-CN 7 3-NO₂ 8 4-NO₂ 9 3-CH₃10 4-CH₃ 11 2-CH₂—Cl 12 4-CH₂—Cl 13 4-Cl 14 4-CF₃ 15 4-CH₂CH₃ 164-(CH₂)₃CH₃ 17 4-C(CH₃)₃ 18 4-N(CH₃)₂ 19 4-OCH₃ 20 4-OCH₂CH₃ 21 4-Ph 222,3-di-CH₃ 23 3,5-di-F 24 3,4-di-F

TABLE 24 (I-2C)

No. R¹⁶ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 25 (I-3C) No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

TABLE 26 (I-4C)

No. R⁷ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 27 (I-5C)

No. R¹⁰ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

TABLE 28 (I-6C)

No. R¹⁰ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

TABLE 29 (I-7C)

No. R²⁷ 1 2-F 2 3-F 3 4-F 4 2-CN 5 3-CN 6 4-CN 7 3-NO₂ 8 4-NO₂ 9 3-CH₃10 4-CH₃ 11 2-CH₂—Cl 12 4-CH₂—Cl 13 4-Cl 14 4-CF₃ 15 4-CH₂CH₃ 164-(CH₂)₃CH₃ 17 4-C(CH₃)₃ 18 4-N(CH₃)₂ 19 4-OCH₃ 20 4-OCH₂CH₃ 21 4-Ph 222,3-di-CH₃ 23 3,5-di-F 24 3,4-di-F

TABLE 30 (I-8C)

No. R¹⁶ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

TABLE 31 (I-9C)

No. R⁷ No. R⁷ 1

12

2

13

3

14

4

15

5

16

6

17

7

18

8

19

9

20

10 

21

11 

22

TABLE 32 (I-10C)

No. R¹⁰ No. R¹⁰ 1

14

2

15

3

16

4

17

5

18

6

19

7

20

8

21

9

22

10 

23

11 

24

12 

25

13 

26

TABLE 33 (I-11C)

No. R²⁷ 1 2-CH₃N(CH₃)₂ 2 3-CH₃N(CH₃)₂ 3 4-CH₃N(CH₃)₂ 4

5

6

7

8

9

TABLE 34 (I-12A)

No. R—AA1—AA2 1

2

3

4

5

6

TABLE 35 (I-12B)

No. R—AA1—AA2 1

2

3

4

5

6

TABLE 36 (I-12C)

No. R—AA1—AA2 1

2

3

4

5

6

In the present invention, isomers are included unless specified. Forexample, alkyl, alkoxy, alkylthio, alkenyl, alkynyl and alkyene includestraight and branched ones. Furthermore, the present invention includesisomers in double bond, ring, fused ring (E, Z, cis, trans), isomers bythe presence of asymmetric carbon etc. (R, S, α, β, enantiomer,diastereomer), optical isomers having optical rotation (D, L, d, 1, +,−), polars by chromatography separation (more polar, less polar),equilibrium compound, a compound of arbitrary ratios of those andracemic mixture.

Salts

The compounds of formula (I) of the present invention may be convertedinto corresponding non-toxic salts by conventional methods. Non-toxicsalts include alkali metal salts, alkaline earth metal salts, aminesalts, acid-addition salts and corresponding quaternary ammonium saltsif the compound of formula (I) contains residues of amino acid.

Non-toxic and water-soluble salts are preferable. Appropriate non-toxicsalts include salts of alkali metals (potassium, sodium etc.), salts ofalkaline-earth metals (calcium, magnesium, etc.), ammonium salts andsalts of pharmaceutically-acceptable organic amines (tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine,benzylamine, phenethylamine, piperidine, monoethanolamine,diethanolamine, tris(hydroxymethyl)aminomethane, lysine, arginine,N-methyl-D-glucamine, etc.

Non-toxic, water-soluble acid-addition salts are preferable. Appropriateacid-addition salts are, inorganic salts such as hydrochloride,hydrobromide, sulfate, phosphate, nitrate, or organic salts such asacetate, trifluoroacetate, lactate, tartrate, oxalate, fumarate, malate,citrate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate,toluenesulfonate, isethionate, glucuronate, gluconate.

The compounds of formula (I) of the present invention or a salt thereofmay be converted into hydrate by a conventional method.

Process for the Preparation of the Compounds of the Present Invention

-   (1) Among the compounds of formula (I), the compound wherein AA¹ and    AA² represent a single bond at the same time and none of R, R⁷, R⁸    and R¹⁰ contains carboxy, hydroxy, amino, thiol, or guanidino, and R    does not represent hydrogen, i.e. the compound of formula (IA)

wherein R^(A), R^(7A), R^(8A) and R^(10A) have the same meanings as R,R⁷, R⁸ and R¹⁰, with proviso that none of them contains carboxy,hydroxy, amino, thiol or guanidino and R^(A) is not hydrogen and theother symbols have the same meanings as above, may be prepared bysubjecting to oxidation reaction a compound of formula (IIA)

wherein all symbols have the same meaning as above.

This oxidation reaction is known, for example,

-   (1) a method of Swern oxidation,-   (2) a method utilizing Dess-Martin reagent, and-   (3) a method utilizing TEMPO reagent, etc.    may be included.

To describe them concretely,

-   (1) the method of Swern oxidation is carried out, for example, in an    inert organic solvent (chloroform, methylene chloride, etc.) by    subjecting to a reaction oxalyl chloride and dimethylsulfoxide at    −78° C. and then subjecting to a reaction the obtained solution with    an alcohol compound, and then subjecting to a reaction with a    tertiary amine such as at a temperature of −78 to 20° C.-   (2) the method utilizing Dess-Martin reagent is carried out, for    example, in an inert organic solvent (chloroform, dichloromethane,    etc.) in the presence of Dess-Martin reagent    (1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3-(1H)-one) at a    temperature of 0˜40° C.-   (3) the method utilizing TEMPO reagent is carried out, for example,    in an inert organic solvent (chloroform, methylene chloride, etc.),    in the presence of TEMPO reagent    (2,2,6,6-tetramethyl-1-piperidinyloxy, free radical) at a    temperature of 20 to 60° C.

These reactions of (1), (2) and (3) are desirably carried out under theatmosphere of an inert gas (argon, nitrogen, etc.) under anhydrousconditions.

The present invention further includes other oxidation reactions whichoxidize alcohol to ketone easily and selectively. For example, Jonesoxidation, oxidation by pyridinium chlorochromate (PCC), sulfurtrioxide-pyridine complex or ones described in “Comprehensive OrganicTransformations”, Richard C. Larock, VCH Publishers, Inc., (1989)604–614, may be used.

-   (2) Among the compounds of formula (I), the compound wherein R is    hydrogen and none of R⁷, R⁸, R¹⁰ contains carboxy, hydroxy, amino,    thiol, or guanidine group, i.e. the compound of formula (IE),

wherein all symbols have the same meaning as above, may be prepared bysubjecting to a deprotection reaction of amino-protective group thecompound among the compounds of formula (IA) prepared according to theabove-described method, wherein R^(A) is a protective group for aminogroup, i.e. the compound of formula (IA-2),

wherein R^(A-2) is a protective group of amino group, and the othersymbols have the same meanings as above.

As protective groups for amino group, for example, benzyloxycarbonyl,t-butoxycarbonyl, trifluoroacetyl, 9-fluorenylmethoxycarbonyl may beincluded, and other groups that can be easily and selectively eliminatedmay also be used instead. For example, the groups described in T. W.Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1991may be used.

Deprotection reaction for protective groups of amino group is known, forexample,

-   1) deprotection reaction under alkaline conditions,-   2) deprotection reaction under acidic conditions,-   3) deprotection reaction by hydration, etc. may be included.    To explain these methods concretely,-   1) deprotection reaction under alkaline conditions is carried out,    for example, in an organic solvent (methanol, tetrahydrofuran,    dioxane, dimethylformamide, etc.) using a hydroxide of alkali metals    (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.),    hydroxide of alkaline earth metals (barium hydroxide, calcium    hydroxide, etc.), organic amine (triethylamine, N-methylmorpholine,    diisopropylethylamine, piperidine, etc.) or a quaternary ammonium    salt (tetrabutyl ammonium fluoride etc.) or a solution thereof or a    mixture thereof at a temperature of 0 to 40° C.;-   2) deprotection reaction under acidic conditions is carried out, for    example, in an organic solvent (methylene chloride, chloroform,    dioxane, ethyl acetate, anisole, etc.), using organic acid (acetic    acid, trifluoroacetic acid, methanesulfonic acid, etc.) or inorganic    acid (hydrochloric acid, sulfuric acid, etc.) or a mixture thereof    (hydrobromic acid/acetic acid, etc.) at a temperature of 0 to 100°    C.;-   3) deprotection reaction by hydration is, for example, carried out    in a solvent (ethers (tetrahydrofuran, dioxane, dimethoxyethane,    diethyl ether, etc.), alcohols (methanol, ethanol, etc.), benzenes    (benzene, toluene, etc.), ketones (acetone, methyl ethyl ketone,    etc.), nitrites such as acetonitrile, amides such as    dimethylformamide, water, ethyl acetate, acetic acid or a mixture of    more than two from above, etc.) in the presence of a catalyst    (palladium-carbon, palladium black, palladium hydroxide, platinum    oxide, Raney nickel, etc.) under the atmosphere of hydrogen of    normal or suppressed pressure, or in the presence of ammonium    formate at a temperature of 0 to 200° C.

As easily understood by those skilled in the art, the compounds of thepresent invention may be easily prepared by selecting these reactions.

-   (3) Among the compounds of formula (I), the compound wherein AA¹ and    AA² represent a single bond at the same time, and at least one of R,    R⁷, R⁸ and R¹⁰ contains carboxy, hydroxy, amino, thiol or guanidino,    or R is hydrogen; i.e. the compound of formula (IB),

wherein R^(B), R^(7B), R^(8B) and R^(10B) have the same meanings as R,R⁷, R⁸ and R¹⁰, but at least one of them contains carboxy, hydroxy,amino, thiol or guanidino or R^(B) is hydrogen and the other symbolshave the same meanings as above, may be prepared by subjecting to adeprotection reaction of a protective group of carboxy, hydroxy, amino,thiol or guanidino, the compound among the compounds of formula (IA)prepared according to the above-described method, wherein at least oneof R^(A), R^(7A), R^(8A) or R^(10A) contains a protected form ofcarboxy, hydroxy, amino, thiol or guanidino, i.e. the compound offormula (IA-1),

wherein R^(A-1), R^(7A-1), R^(8A-1) and R^(10A-1) have the same meaningsas R^(A), R^(7A), R^(8A) and R^(10A) respectively, but at least one ofR^(A-1), R^(7A-1), R^(8A-1) and R_(10A-1) contains a protected form ofcarboxy, hydroxy, amino, thiol or guanidino, or R^(A-1) is a protectivegroup of amino, and the other symbols have the same meanings as above,or the compound among the compound of formula (IE) prepared according tothe above-described method, wherein at least one of R^(7A), R^(8A) andR^(10A) contains a protected form of carboxy, hydroxy, amino, thiol orguanidino; i.e. the compound of formula (IE-1),

wherein all symbols have the same meanings as above.

Protective groups for carboxy include, for example, methyl, ethyl,t-butyl and benzyl.

Protective groups for hydroxy include, for example, methoxymethyl,2-tetrahydropyranyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, acetyland benzyl.

Protective groups for amino include those shown above.

Protective groups for thiol include, for example, benzyl, methoxybenzyl,methoxymethyl, 2-tetrahydropyranyl, diphenylmethyl and acetyl.

Protective groups for guanidino include, for example, benzyloxycarbonyl,t-butoxycarbonyl and 9-fluorenylmethoxycarbonyl. As protective groupsfor carboxy, hydroxy, amino, thiol or guanidino group, other groups thanabove listed, if easily and selectively eliminated, may also be usedinstead. For example, the groups described in T. W. Greene, ProtectiveGroups in Organic Synthesis, Wiley, New York, 1991 may be used.

Deprotection reactions of the protective groups for carboxy, hydroxy,amino, thiol or guanidino are well known, for example,

-   1) a deprotection reaction under alkaline conditions,-   2) a deprotection reaction under acidic conditions,-   3) a deprotection reaction by hydration,-   4) a deprotection reaction of silyl-containing groups, etc. The    methods of 1), 2) and 3) are carried out by the methods described    above.-   4) A deprotection reaction of silyl-containing group is carried out,    for example, in a water-miscible organic solvent (tetrahydrofuran,    acetonitrile, etc.) using tetrabutylammonium fluoride at a    temperature of 0 to 40° C.

As easily understood by those skilled in the art, the target compoundsof the present invention may be easily prepared by selecting thesereactions.

-   (4) Among the compounds of formula (I), the compound wherein AA¹ and    AA² do not represent a single bond at the same time, and R, AA¹,    AA², R⁷, R⁸ and R¹⁰ represent a group which do not contain carboxy,    hydroxy, amino, thiol, guanidino; i.e. the compound of formula (IC),

wherein R^(C), AA^(1C) and AA^(2C) have the same meanings as R, AA¹ andAA², but none of them contains carboxy, hydroxy, amino, thiol, guanidinoand AA^(1C) and AA^(2C) do not represent a single bond at the same timeand R^(C) does not represent a hydrogen atom. The other symbols have thesame meanings as above, may be prepared according to the following [1]or [2].

-   [1] The compound of formula (IC) may be prepared by subjecting to an    oxidation reaction the compound of formula (IIC),

wherein all symbols have the same meanings as above.

Oxidation reaction is carried out according to the method abovedescribed.

-   [2] The compound of formula (IC) may be prepared by subjecting to    amidation reaction the compound of formula (IE) and the compound of    formula (X),    R^(C)-AA^(1C)-AA^(2C)-OH  (X)    wherein all symbols have the same meanings as above.

Amidation reaction is known, for example,

-   1) a method using acid halide,-   2) a method using mixed anhydride,-   3) a method using a condensing agent (EDC, DCC, etc.), etc.

To explain these methods concretely,

1) the method using acid halide is carried out, for example, bysubjecting to a reaction carboxylic acid and acid-halogenating agent(oxalyl chloride, thionyl chloride, etc.) in an organic solvent(chloroform, methylene chloride, diethyl ether, tetrahydrofuran, etc.)or without a solvent, at a temperature between −20° C. and refluxingtemperature, and then subjecting to a reaction thus obtained acid halidein the presence of tertiary amine (pyridine, triethylamine,dimethylaniline, dimethylaminopyridine, etc.) in an inert organicsolvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran,etc.) at a temperature between 0 to 40° C.

And it may be carried out by subjecting to a reaction with acid halidein an organic solvent (dioxane, tetrahydrofuran, etc.) using an aqueousalkali solution (an aqueous solution of sodium bicarbonate or sodiumhydroxide, etc.) at a temperature between 0 to 40° C.

2) The method using mixed anhydride is carried out, for example, bysubjecting to a reaction in an organic solvent (chloroform, methylenechloride, diethyl ether, tetrahydrofuran, etc.) or without a solvent, inthe presence of tertiary amine (pyridine, triethylamine,dimethylaniline, dimethylaminopyridine, etc.), carboxylic acid with acidhalide (pivaloyl chloride, tosyl chloride, mesylchloride, etc.) or acidderivative (chloroethyl formate, chloroisobutyl formate, etc.) at atemperature between 0 to 40° C., and then subjecting to a reaction thusobtained mixed anhydride with amine in an organic solvent (chloroform,methylene chloride, diethyl ether, tetrahydrofuran, etc.) at atemperature between 0 to 40° C.

3) The method using a condensing agent is carried out, for example, inan organic solvent (chloroform, methylene chloride, dimethylformamide,diethyl ether, tetrahydrofuran, etc.) or without a solvent, in thepresence or absence of a tertiary amine (pyridine, triethylamine,dimethylaniline, dimethylaminopyridine, etc.), using a condensing agent(1,3-dicychlorohexylcarbodiimide (DCC),1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC),1,1′-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodide,etc.) in the presence or absence of 1-hydroxybenzotriazole (1-HOBt), bysubjecting to a reaction carboxylic acid and amine at a temperaturebetween 0 and 40° C.

The reactions 1), 2) and 3) are desirably carried out under atmosphereof inert gas (argon, nitrogen, etc.) and anhydrous conditions.

-   (5) Among the compounds of formula (I), the compound wherein AA¹ and    AA² do not represent a single bond at the same time, and at least    one of R, AA¹, AA², R⁷, R⁸, R¹⁰ contains carboxy, hydroxy, amino,    thiol, guanidino, i.e. the compound of formula (ID),

wherein R^(D), AA^(1D), AA^(2D), R^(7D), R^(8D) and R^(10D) have thesame meaning as R, AA¹, AA², R¹, R⁸ and R¹⁰ respectively, with provisothat AA^(1D) and AA^(2D) do not represent a single bond at the sametime, and at least one of R^(D), AA^(1D), AA^(2D), R^(7D), R^(8D) orR^(10D) represents a group which contains carboxy, hydroxy, amino,thiol, guanidino, or R^(D) is hydrogen. And the other symbols have thesame meanings as above.) may be prepared by subjecting to a deprotectionreaction of protective groups of carboxy, hydroxy, amino, thiol, orguanidino the compound among the compounds of formula (IC), which wasprepared by the previous method, wherein at least one of R, AA^(1C),AA^(2C), R^(7A), R^(8A) or R^(10A) contains a protected form of carboxy,hydroxy, amino, thiol or guanidino, i.e. the compound of formula (IC-1),

wherein R^(C-1), AA^(1C-1), AA^(2C-1), R^(7C-1), R^(8C-1) and R^(10C-1)have the same meanings as R^(C), AA^(1C), AA^(2C), R^(7A), R^(8A) andR^(10A), with proviso that R^(C-1), R^(1C-1), AA^(2C-1), R^(7C-1),R^(8C-1) and R^(10C-1) contains at least one protected carboxy, hydroxy,amino, thiol or guanidino, or R^(C-1) is a protective group of amino.And the other symbols have the same meaning as above.

Deprotection reaction of carboxy, hydroxy, amino, thiol, guanidino iscarried out as hereinbefore described.

And the compounds of formula (IIA) and (IIC) may be prepared accordingto the method by the following reaction scheme (1).

In the reaction scheme (1), all symbols have the same meanings ashereinbefore described.

The compound of formula (III) may be prepared according to the method bythe following reaction scheme (2).

In the reaction scheme (2), Q is t-butoxycarbonyl or benzyloxycarbonyl.The other symbols have the same meanings as hereinbefore described.

The compound of formula (X-8) may be prepared according to the method bythe following reaction scheme (3).

In the reaction scheme (3), R^(X) is methyl, ethyl or t-butyl. The othersymbols have the same meanings as above.

Among the compounds of formula (III), the compound wherein Z ring is

and R⁹ is hydrogen atom, i.e. the compound of formula (III-1),

wherein all symbols have the same meanings as above, may be prepared bythe method in the following reaction scheme (4).

In the reaction scheme (4), Q¹ is t-butoxycarbonyl, Q² is methyl orethyl, and

is a protective group for amino alcohol (for example, Q³ is methyl orethyl).

Among the compounds of formula (IIA) and (IIC), the compound wherein Zis

i.e. the compound of formula (IIA-1),

wherein all symbols have the same meanings as above, and the compound offormula (IIC-1),

wherein all symbols have the same meanings as above, may be prepared bythe methods described by the reaction schemes (5) and (6).

In the reaction schemes (5) and (6), Q³ is a protective group forhydroxy (t-butyldimethylsilyl, trimethylsilyl, etc.) and the othersymbols have the same meanings as above.

The starting materials, i.e. the compounds of formula (X), (X-1) and(X-4) are known per se or may be prepared by known methods.

All reactions in the reaction schemes may be carried out by conventionalmethods. Other starting materials and agents in the present inventionare known per se or may be prepared by conventional methods.

In each reaction of the present specification, reaction products may bepurified by conventional techniques. For example, purification may becarried out by distillation under atmospheric or reduced pressure, byhigh performance liquid chromatography, thin layer chromatography orcolumn chromatography using silica gel or magnesium silicate, by washingor by recrystallization, etc. Purification may be carried out after eachreaction, or after a series of reactions.

Pharmacological Activity of the Compounds of the Present Invention

It was confirmed by the following experiments that the compounds of thepresent invention of formula (I) have an inhibitory activity againstcysteine protease.

(i) Measurement of Cathepsin K Inhibitory Activity

65 μL of Cathepsin K enzyme reaction buffer (50 mmol/L of2-(N-morpholino)ethanesulfonate, 2 mmol/L of ethylenediaminetetraacetate (EDTA) and 4 mmol/L of dithiothreitol (DTT) were mixed toadjust to pH 5.5), 5 μL of cysteine protease inhibitor solution ofseveral concentrations, 20 μL of synthesized substrate(t-butyloxycarbonyl-L-alanyl-glycyl-L-prolyl-L-arginine-4-methyl-chromanyl-7-amide)solution of several concentrations and 10 μL of cathepsin K enzymesolution were mixed and the increase of fluorescence intensity whenreacted at 37° C. was measured (λex (excitation wavelength)=355 nm, λem(fluorescence wavelength)=460 nm). As to the substrate and the compoundof the present invention, enzyme reactions were carried out incombination of several appropriate concentrations and Dixon plotting wasprepared, to define the absolute value of X-coordinate of theintersection point of the graph as Ki value.

It was confirmed that the compound of the present invention of formula(I) had an inhibitory activity more than 50% at 10 μM. For example, theKi values of inhibitory activity of the compounds of example 3 andexample 7 (2) were, 1.3 nM and 14 nM respectively.

(ii) Measurement of Cathepsin B Inhibitory Activity

10 μL of Synthesized substrate(carbobenzoxy-L-arginyl-L-arginine-4-methyl-chromanyl-7-amide orcarbobenzoxy-L-phenylalanyl-L-arginine-4-methyl-chromanyl-7-amide)solution of several concentrations, 10 μL of cysteine protease inhibitorsolution of several concentrations, 70 μL of cathepsin B enzyme reactionbuffer (mixture of 400 mmol/L in acetic acid, 4 mmol/L EDTA, 8 mmol/LDDT to adjust to pH 5.5) and 10 μL of cathepsin B enzyme solution weremixed and the increase of fluorescence intensity was measured (λex(excitation wavelength)=355 nm, λem (fluorescence wavelength)=460 nm)when reacted at 37° C.

It was confirmed that the compound of the present invention of formula(I) had an inhibitory activity more than 50% at 10 μM. For example, theinhibitory activity of the compound of example 3 (5) was 100% at 1 μM.

(iii) Measurement of Cathepsin S Inhibitory Activity

10 μL of synthesized substrate(carbobenzoxy-L-leucyl-L-leucyl-L-arguinine-4-methyl-chromanyl-7-amide)solution and 5 μL of cysteine protease inhibitor solution of severalconcentrations, 75 μL of cathepsin S enzyme reaction buffer (100 mmol/Lof sodium phosphate, 2 mmol/L of EDTA, 2 mmol/L of DTT were mixed toadjust to pH 6.5) and 10 μL of cathepsin S enzyme solution were mixedand the increase of fluorescence intensity was measured (λex (excitationwavelength)=355 nm, λem (fluorescence wavelength)=460 nm) when reactedat 37° C.

It was confirmed that the compound of the present invention of formula(I) has an inhibitory effect more than 50% at 10 μM. For example, theinhibitory activity of the compound of example 3 (7) was 100% at 1 μM.

(iv) Measurement of Cathepsin L Inhibitory Activity

5 μL of Synthesized substrate(carbobenzoxy-L-phenylalanyl-L-arguine-4-methyl-chromanyl-7-amide orL-prolyl-L-phenylalanyl-L-arguinine-4-methyl-chromanyl-7-amide) solutionand 5 μL of cysteine protease inhibitor solution of severalconcentrations, 80 μL of cathepsin L enzyme reaction buffer (400 mmol/Lacetic acid, 4 mmol/L EDTA, 8 mmol/L DTT were mixed to adjust to pH 5.5)and 10 μL of cathepsin L enzyme solution were mixed and the increase offluorescence intensity was measured (λex (excitation wavelength)=355 nm,λem (fluorescence wavelength)=460 nm) when reacted at 37° C.

It was confirmed that the compound of the present invention of formula(I) had an inhibitory activity of more than 50% at 10 μM. For example,the inhibitory activity of the compound of example 1(21) was 92% at 1μM.

(v) Measurement of Calpain Inhibitory Activity

The activity was measured according to the method described inCalcium-depending protease, Seibutsukagaku-Jikkenhou (BiochemistryExperimental Method) Tanpakubunkaikouso (Protease) I, 57 (1993).

(vi) Measurement of Caspase-1 Inhibitory Activity

50 μL of caspase-1 enzyme reaction solution (20 mmol/L of4-(2-hydroxyethyl)-1-piperazinethanesulfonate-sodium hydroxide buffer pH7.4, 10 mmol/L of potassium chloride, 1.5 mmol/L of magnesium chloride,0.1 mmol/L EDTA, 10% glycerol) and 50 μL of cysteine protease inhibitorsolution of several concentrations, 50 μL of caspase-1 enzyme solutionand 100 μL of synthesized substrate(acetyl-L-tyrosinyl-L-valinyl-L-alanyl-L-asparticacid-4-methyl-chromanyl-7-amide) solution of several concentrations werereacted at 37° C. and the fluorescence intensity was measured (λex(excitation wavelength)=355 nm, λem (fluorescence wavelength)=460 nm).

(vii) Investigation in Bone Resorption Inhibitory Activity Using MouseCalvaria Cultivation System

Mouse neonatal calvaria was cultured in D-minimum essential mediumcontaining cysteine protease inhibitor (mixture of Penicillin Gpotassium (final concentration 100 U/ml), streptomycin sulfate (finalconcentration 0.1 mg/ml), bovine serum albumin (final concentration0.1%), glutamine (final concentration 0.3 mg/ml) in D-minimal essentialmedium) with incitant (parathyroid hormone (PTH) or arotinoid) at 37° C.and the calcium concentration in the culture medium was measured.

(viii) Bone Resorption Pit Formation Test Using Rabbit Osteoclast Cells

Osteoclast cells collected from rabbit bones were sowed over slices ofbovine cortical bone, dentine or teeth of toothed whale and werecultured at 37° C. in α-minimal essential medium containing finalconcentration 5% of fetal bovine serum and various concentrations ofcysteine protease inhibitor. The pits formed on the slices by theosteoclast cells were observed and at the same time type-I collagenC-terminal telopeptide (CTx) concentration in culture medium wasmeasured.

(ix) Investigation of Immune Reaction Inhibitory Effect UsingAntigen-sensitized Mouse Spleen Cells

Spleen cells were collected from mice sensitized by ovalbumin (OVA)several times. Inhibitory effect of cysteine protease inhibitors againstimmune response induced by OVA stimulus was investigated, using cytokineconcentration and immunoglobulin concentration in culture solution asindicators.

(x) Investigation in Inhibitory Effect Against Bone Resorption Using theRat PTH Hypercalcemia Model

The effect of cysteine protease inhibitor (compulsory oraladministration, intraperitoneal administration) on bone resorption whichwas promoted by intravenous administration of parathyroid hormone (PTH)solution (30 μg/ml) was investigated in rats, using calciumconcentration in blood as an indicator.

(xi) Studies on Bone Resorption Inhibitory Effect Using TPTx Rat PTHrP-Induced Hypercalcemia Model

The effect of cysteine protease inhibitor (compulsory oraladministration, intraperitoneal administration) on bone resorption,promoted by subcutaneous administration of parathyroid hormone relatedpeptide (PTHrP) to a fasting rat (thyroparathyroidectomized; TPTx) wasinvestigated, using calcium concentration in blood as an indicator.

Toxicity

The toxicity of the compounds of the present invention is very low andtherefore it was confirmed that the compounds are safe forpharmaceutical use.

INDUSTRIAL APPLICABILITY

Application to Pharmaceuticals

The compound of formula (I) of the present invention has an inhibitoryactivity against cysteine proteases, and therefore it is useful as anagent for the prophylaxis and/or treatment of inflammatory diseases(periodontitis, arthritis, inflammatory bowel diseases, infectiousdiseases, pancreatitis, hepatitis, glomerulonephritis, endocarditis,myocarditis, etc.), diseases induced by apoptosis (graft versus hostdiseases, rejection of an organ transplantation, acquired immunedeficiency syndrome (AIDS), AIDS-related complex (ARC), adult T cellleukemia, hairy cells leukemia, spondylopathy, disorders of respiratoryapparatus, arthritis, HIV or HTLV-1 related diseases such as uveitis,virus-related diseases such as hepatitis C, cancer, collagenosis(systemic lupus erythematosus, rheumatoid arthritis, etc.), ulcerativecolitis, Sjoegren's syndrome, primary biliary cirrhosis, spontaneousthrombocytopenic purpura, autoimmune hemolytic anemia, myastheniagravis, autoimmune diseases such as insulin dependent (type I) diabetes,diseases accompanying thrombocytopenia (osteomyelodysplasia syndrome,periodic thrombocytopenia, aplastic anemia, spontaneousthrombocytopenia, disseminated intravascular coagulation (DIC), etc.),hepatic diseases such as viral hepatitis (type A, B, C, F, etc.) orhepatitis medicamentosa and cirrhosis, dementia such as Alzheimer'sdiseases and Alzheimer's senile dementia, cerebrovascular injury, nervedegeneration diseases, adult acute respiratory distress syndrome,infectious diseases, prostatomegaly, hysteromyoma, bronchial asthma,arteriosclerosis, all kinds of lusus naturae, nephropathy, senilecataract, chronic fatigue syndrome, myodystrophy, peripheral neuropathy,etc.), diseases induced by disorders of immune response (graft versushost diseases, rejection of an organ transplantation, allergic diseases(bronchial asthma, atopic dermatitis, allergic rhinitis, pollinosis,diseases induced by house dusts, irritable pneumonia, food allergy,etc.), psoriasis, rheumatoid arthritis, etc.), autoimmune diseases(insulin-dependent (type I) diabetes, systemic lupus erythematosus,Hashimoto's diseases, multiple sclerosis, etc.), desease by decomposingvarious proteins which compose the organism (myodystrophy, cataract,periodontitis, hepatocyte desease by bile acid such as cholestaticcirrhosis, etc.), decomposition of alveolus elastica such as pulmonaryemphysema, ischemic diseases (brain ischemia, brain disorders byischemic reperfusion, myocardial infarction, ischemic hepatopathy,etc.), shock (septic shock, systemic inflammation response syndrome,endotoxin shock, acidosis, etc.), circulatory system disorders(arteriosclerosis, restenosis after percutaneous transluminal coronaryangioplasty (PTCA), etc.)), blood coagulation disorders(thrombocytopenic purpura, hemolytic uremic syndrome, etc.), malignanttumor, acquired immune deficiency syndrome (AIDS) and AIDS-relatedcomplex (ARC), parasitic diseases such as malaria, nerve degenerativediseases (Alzheimer-type dementia, Huntington's chorea, Parkinson'sdiseases, multiple sclerosis, traumatic encephalopathy, traumaticspondylopathy, etc.), pulmopathy such as fibroid lungs, bone resorptiondiseases (osteoporosis, rheumatoid arthritis, arthritis, osteoarthritis,hypercalcemia, osteometastasis of cancer etc.), endocrinesthenia such ashyperthyroidism.

For the purpose described above, the compounds of formula (I), of thepresent invention, non-toxic salts thereof, acid addition salts thereofor hydrates thereof may normally be administered systemically orlocally, usually by oral or parenteral administration.

The doses to be administered are determined depending upon, for example,age, body weight, symptom, the desired therapeutic effect, the route ofadministration, and the duration of the treatment. In the human adult,the doses per person at a time are generally from 1 mg to 1000 mg, byoral administration, up to several times per day, and from 1 mg to 100mg, by parenteral administration (preferably intravenousadministration), up to several times per day, or continuousadministration for from 1 to 24 hours per day from vein.

As mentioned above, the doses to be used depend upon various conditions.Therefore, there are cases wherein doses lower than or greater than theranges specified above may be used.

The compounds of the present invention may be administered in the formof, for example, solid compositions, liquid compositions or othercompositions for oral administration, injections, liniments orsuppositories for parenteral administration.

Solid compositions for oral administration include compressed tablets,pills, capsules, dispersible powders and granules.

Capsules include hard capsules and soft capsules.

In such solid compositions, one or more of the active compound(s) may beused as a dosage form, as is normal practice, to admix with excipient(e.g. lactose, mannitol, glucose, microcrystalline cellulose, starch),combining agents (hydroxypropyl cellulose polyvinyl pyrrolidone ormagnesium metasilicate aluminate), disintegrating agents (e.g. cellulosecalcium glycolate), lubricating agents (e.g. magnesium stearate),stabilizing agents, agents to assist dissolution (e.g. glutamic acid orasparatic acid) and the like. The agents may, if desired, be coated withcoating agents (e.g. sugar, gelatin, hydroxypropyl cellulose orhydroxypropylmethyl cellulose phthalate), or be coated with two or morefilms. Further, coating may include containment within capsules ofabsorbable materials such as gelatin.

Liquid compositions for oral administration include pharmaceuticallyacceptable solutions, suspensions, emulsions, syrups and elixirs. Insuch compositions, one or more of the active compound(s) are dissolved,suspended or emulsified in diluent commonly used (e.g. purified water,ethanol or mixture thereof). Furthermore, such liquid compositions mayalso comprise wetting agents or suspending agents, emulsifying agents,sweetening agents, flavouring agents, perfuming agents, preservingagents buffer agent etc.

Injections for parenteral administration include solutions, suspensions,emulsions and solids which are dissolved or suspended to use at a timeto use. One or more of the active compound(s) in injections aredissolved, suspended and emulsified in a solvent. The solvents are, forexample, distilled water for injection, physiological salt solution,vegetable oil, propylene glycol, polyethylene glycol, alcohol such asethanol or mixture thereof. Moreover the injections may also includestabilizing agents, agents to assist dissolution (e.g. glutamic acid,aspartic acid or POLYSORBATE80 (registered trade mark)), suspendingagents, emulsifying agents, soothing agents, buffer agents, preservingagents, etc. They are sterilized in the last process or manufactured andprepared by sterile procedure. They may also be manufactured in the formof sterile solid compositions such as freeze-dried one and they may besterilized or dissolved to use in sterile distilled water for injectionor some other solvents immediately before use.

Other compositions for parenteral administration include liquids forexternal use, and ointment, endermic liniments, inhale, spray,suppositories for rectal administration and pessaries for vaginaladministration which comprise one or more of the active compound(s) andare prescribed by methods known per se.

Spray compositions may comprise additional substances other thandiluents: e.g. stabilizing agents (e.g. sodium sulfite hydride),isotonic buffers (e.g. sodium chloride, sodium citrate or citric acid).For preparation of such spray compositions, for example, the methoddescribed in the U.S. Pat. No. 2,868,691 or 3,095,355 may be used.

BEST MODE FOR CARRYING OUT THE INVENTION

The following Reference Examples and Examples illustrate the presentinvention, but do not limit the present invention.

The solvents in the parentheses show the eluting or developing solventsand the ratios of the solvents used are by volume in chromatographicseparations or TLC.

The solvents in the parentheses in NMR show the solvents used inmeasurement. TBS represents t-butyldimethylsilyl.

REFERENCE EXAMPLE 1 (2S)-2-(N-t-butoxycarbonylamino)-4-methylpentanol

To a solution of (2S)-2-amino-4-methylpentanol((L)-leucinol) (20 g) intetrahydrofuran (1000 ml) was added di-t-butyldicarbonate (43 ml)dropwise at 0° C. and the mixture was stirred for 1.5 hours at roomtemperature. The reaction mixture was concentrated to give the crudeproduct having the following physical data of the title compound.

TLC: Rf 0.50 (chloroform:methanol=10:1);

NMR (CDCl₃): δ 4.58 (br, 1H), 3.81–3.45 (m, 3H), 1.80–1.60 and 1.37–1.25(each m, totally 3H), 1.45 (s, 9H), 0.95–0.91 (m, 6H).

REFERENCE EXAMPLE 2 (2S)-2-(N-t-butoxycarbonylamino)-4-methylpentanal

To a solution of the compound prepared in Reference Example 1 indimethylsulfoxide (344 ml) were added triethylamine (72 ml) and sulfurtrioxide-pyridine complex (82 g) in dimethylsulfoxide (280 ml) at roomtemperature and the mixture was stirred for 1 hour. The reaction mixturewas poured into ice-water and was extracted with ethyl acetate. Theorganic layer was washed with 10% aqueous solution of citric acid, waterand saturated aqueous solution of sodium chloride successively, driedover anhydrous sodium sulfate and was concentrated to give a crudeproduct of the title compound having the following physical data.

TLC: Rf 0.45 (chloroform:methanol=10:1);

NMR (CDCl₃): δ 9.59 (s, 1H), 4.91 (br, 1H), 4.12 (br, 1H), 1.80–1.60 and1.40–1.30 (each m, totally 3H), 1.46 (s, 9H), 1.00–0.87 (m, 6H).

REFERENCE EXAMPLE 3(3S)-3-(N-t-butoxycarbonylamino)-2-hydroxy-5-methylhexanenitrile

To a solution of the crude compound prepared in Reference Example 2 inmethanol (180 ml) were added acetonecyanohydrine (19 ml) and potassiumcarbonate (4.7 g) at 0° C. and the mixture was stirred for 1 hour atroom temperature. The reaction mixture was concentrated and the residuewas extracted with ethyl acetate and water. The organic layer was washedwith water and saturated aqueous solution of sodium chloride, dried overanhydrous sodium sulfate and was concentrated. The residue was purifiedby column chromatography on silica gel (n-hexane:ethyl acetate=3:1) togive the title compound (33.6 g) having the following physical data.

TLC: Rf 0.40 (n-hexane:ethyl acetate=3:1);

NMR (CDCl₃): δ 4.85–4.80 (m, 1H), 4.60–4.45 (m, 1H), 4.00–3.70 (m, 1H),1.80–1.40 (m, 3H), 1.45 and 1.43 (each s, totally 9H), 1.00–0.90 (m,6H).

REFERENCE EXAMPLE 4 (3S)-3-amino-2-hydroxy-5-methylhexanoic AcidHydrochloride

To the compound prepared in Reference Example 3 (33.6 g) was added conc.hydrochloric acid (300 ml) and the mixture was stirred for 5 hours at80° C. The reaction mixture was concentrated to give a crude product ofthe title compound having the following physical data.

TLC: Rf 0.30 (chloroform:methanol:water=6:4:1).

REFERENCE EXAMPLE 5 (3S)-3-amino-2-hydroxy-5-methylhexanoic Acid MethylEster Hydrochloride

To methanol (1000 ml) was added thionyl chloride (92 ml) at −40° C. andthe mixture was stirred for 10 minutes. To a solution of the compoundprepared in Reference Example 4 in methanol (250 ml) was added the aboveprepared solution at −10° C. and the mixture was stirred for 4 hours atroom temperature. The reaction mixture was concentrated to give a crudeproduct of the title compound having the following physical data.

TLC: Rf 0.50 (chloroform:methanol:water=6:4:1).

REFERENCE EXAMPLE 6(3S)-3-(N-t-butoxycarbonylamino)-2-hydroxy-5-methylhexanoic Acid MethylEster

To a solution of the crude compound prepared in Reference Example 5 (32g) in methylene chloride (300 ml) were added triethylamine (20 ml) anddi-t-butyl carbonate (34 ml) at 0° C. and the mixture was stirred for 4hours at room temperature. To the reaction mixture was added water andwas extracted with ethyl acetate. The organic layer was washed with a10% aqueous solution of citric acid, a saturated aqueous solution ofsodium bicarbonate, water and saturated aqueous solution of sodiumchloride successively, dried over anhydrous sodium sulfate and wasconcentrated. The residue was purified by column chromatography onsilica gel (n-hexane:ethyl acetate=3:1) to give the title compound (28g) having the following physical data.

TLC: Rf 0.40 and 0.35 (n-hexane:ethyl acetate=3:1);

NMR (CD₃OD): δ 4.10–4.09 (m, 1H), 4.04–3.95 and 3.93–3.85 (each m,totally 1H), 3.72 and 3.70 (each s, totally 3H), 1.70–1.08 (m, 3H), 1.43and 1.40 (each s, totally 9H), 0.98–0.82 (m, 6H).

REFERENCE EXAMPLE 7(3S)-3-(N-t-butoxycarbonylamino)-2-hydroxy-5-methylhexanoic AcidHydrazide

To hydrazine hydrate (99 ml) was added the compound prepared inReference Example 6 (28 g) in methanol (110 ml) at 0° C. dropwise andthe mixture was stirred for 1 hour at room temperature. To the reactionmixture was added water and was extracted with methylene chloride. Theorganic layer was washed with saturated aqueous solution of sodiumchloride, dried over anhydrous sodium sulfate and was concentrated togive the title compound (21 g) having the following physical data.

TLC: Rf 0.40 (chloroform:methanol:water=9:1:0.1);

NMR (CD₃OD): δ 4.10 (d, J=3.6 Hz, 0.5H), 4.00–3.90 (m, 1.5H), 1.70–1.30(m, 3H), 1.43 and 1.41 (each s, totally 9H), 0.95–0.88 (m, 6H).

REFERENCE EXAMPLE 8(2S)-2-(N-t-butoxycarbonylamino)-4-methyl-1-(2-oxo-1,3,4-oxadiazolin-5-yl)pentanol

To a solution of the compound prepared in Reference Example 7 (20 g) and1,1-carbonyldiimidazole (14 g) in tetrahydrofuran (400 ml) was addedtriethylamine (12 ml) at 0° C. and the mixture was stirred for 5 hoursat room temperature. To the reaction mixture was added a 10% aqueoussolution of citric acid and was extracted with ethyl acetate. Theorganic layer was washed with a saturated aqueous solution of sodiumbicarbonate, water and saturated aqueous solution of sodium chloridesuccessilvely, dried over anhydrous sodium sulfate and was concentrated.The residue was purified by column chromatography on silica gel(chloroform:methanol=20:1) to give the title compound (17 g) having thefollowing physical data.

TLC: Rf 0.50 and 0.45 (chloroform:methanol=10:1);

NMR (CDCl₃): δ 4.87 and 4.80 (each brd, each J=9.3 Hz, totally 1H),4.60–4.50 (m, 1H), 4.10–3.90 (m, 1H), 1.80–1.30 (m, 3H), 1.45 and 1.41(each s, totally 9H), 1.00–0.80 (m, 6H).

REFERENCE EXAMPLE 9(2S)-2-(N-t-butoxycarbonylamino)-4-methyl-1-[3-2-methylpropyl-2-oxo-1,3,4-oxadiazolin-5-yl]pentanol

To a solution of the compound prepared in Reference Example 8 (4.5 g) inN,N-dimethylformamide (44 ml) was added potassium carbonate (4.1 g) andthe mixture was stirred for 30 minutes at 0° C. To the reaction mixturewas added isobutyl iodide (2.0 ml) and the mixture was stirred for 6hours at 50° C. To the reaction mixture was added water and extractedwith ethyl acetate. The organic layer was washed with water andsaturated aqueous solution of sodium chloride successively, dried overanhydrous sodium sulfate and was concentrated. The residue was purifiedby column chromatography on silica gel (n-hexane:ethyl acetate=2:1) togive a crude product of the title compound (5.2 g) having the followingphysical data.

TLC: Rf 0.35 (n-hexane:ethyl acetate=3:1);

NMR (CDCl₃): δ 4.80–4.50 (m, 2H), 4.10–3.80 (m, 1H), 3.50–3.45 (m, 2H),2.10–2.05 (m, 1H), 1.70–1.30 (m, 3H), 1.45 and 1.40 (s, 9H), 1.00–0.90(m, 12H).

REFERENCE EXAMPLE 10(2S)-2-amino-4-methyl-1-[3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl]pentanolHydrochloride

To a solution of the compound prepared in Reference Example 9 (1.01 g)in methanol (3 ml) was added 4N hydrochloric acid-ethyl acetate (11 ml)and the mixture was stirred for 30 minutes at room temperature. Thereaction mixture was concentrated to give a crude product of the titlecompound having the following physical data.

TLC: Rf 0.46 (chloroform:methanol:water=6:4:1).

REFERENCE EXAMPLE 11(2S)-N-[(2S)-1-hydroxy-4-methyl-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

To a solution of N-benzyloxycarbonyl-(L)-leucine (901 mg),1-hydroxybenzotriazole (581 mg) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (651 mg) inN,N-dimethylformamide (4 ml) was added a solution of the compoundprepared in Reference Example 10 in N,N-dimethylformamide (2 ml)dropwise at 0° C. and thereto was added N-methyl morpholine (0.37 ml) at0° C. and the mixture was stirred overnight at room temperature. To thereaction mixture was added water and was extracted with ethyl acetate.The organic layer was washed with a saturated aqueous solution of sodiumbicarbonate, water and saturated aqueous solution of sodium chloridesuccessively, dried over anhydrous sodium sulfate and was concentrated.The residue was purified by column chromatography on silica gel(n-hexane:ethyl acetate=2:1) to give the title compound (1.28 g) havingthe following physical data.

TLC: Rf 0.70 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.40–7.30 (m, 5H), 6.50–6.38 (m, 1H), 5.20–5.08 (m, 3H),4.60–4.10 (m, 3H), 3.50–3.40 (m, 2H), 2.20–2.00 (m, 1H), 1.70–1.20 (m,6H), 1.00–0.80 (m, 18H).

EXAMPLE 1(2S)-N-[(2S)-2-(4-methyl-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

To a solution of the compound prepared in Reference Example 11 (1.23 g)in methylene chloride (17 ml) were added TEMPO reagent(2,2,6,6-tetramethyl-1-piperidinyloxy, free radical) (38 mg) and(diacetoxyiodo)benzene (1.57 g), and the mixture was stirred for 3.5hours at room temperature. To the reaction mixture was added a saturatedaqueous solution of sodium thiosulfate and was extracted with ethylacetate. The organic layer was washed with water and saturated aqueoussolution of sodium chloride successively, dried over anhydrous sodiumsulfate and was concentrated. The residue was purified by columnchromatography on silica gel (n-hexane:ethyl acetate=3:1) to give thecompound of the present invention (1.12 g) having the following physicaldata.

TLC: Rf 0.50 (n-hexane:ethyl acetate=3:1);

NMR (CDCl₃): δ 7.40–7.30 (m, 5H), 6.51 (brd, J=7.5 Hz, 1H), 5.33 (ddd,J=9.9, 7.5, 4.2 Hz, 1H), 5.20–5.10 (m, 1H), 5.12 (s, 2H), 4.28–4.15 (m,1H), 3.68 (dd, J=13.8, 6.9 Hz, 1H), 3.63 (dd, J=13.8, 6.9 Hz, 1H),2.25–2.13 (m, 1H), 1.75–1.43 (m, 6H), 1.00–0.88 (m, 18H).

EXAMPLE 1 (1) TO EXAMPLE 1 (22)

By the same procedure as described in Reference Example 9→ReferenceExample 10→Reference Example 11→Example 1, using the compound preparedin Reference Example 8 or2-(N-t-butoxycarbonylamino)-4-methyl-1-(2-oxo-(1,3,4-oxadiazolin)-5-yl)pentanol,and isobutyl bromide or a corresponding halogenated compound, thecompounds of the present invention having the following data wereobtained.

EXAMPLE 1 (1)(2S)-N-[4-methyl-1-(3-methyl-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.52 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.35 (s, 5H), 6.67 and 6.50 (each brd, J=6.6 Hz, totally1H), 5.30 (m, 1H), 5.20–5.03 (m, 3H), 4.22 (m, 1H), 3.55 and 3.54 (eachs, totally 3H), 1.84–1.40 (m, 6H), 1.05–0.84 (m, 12H).

EXAMPLE 1 (2)(2S)-N-[4-methyl-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.21 (n-hexane:ethyl acetate=4:1);

NMR (CDCl₃): δ 7.35 (s, 5H), 6.61 and 6.43 (each br, totally 1H), 5.33(m, 1H), 5.15–4.95 (m, 3H), 4.21 (m, 1H), 3.68 (dd, J=14.1, 7.2 Hz, 1H),3.63 (dd, J=14.1, 7.2 Hz, 1H), 2.18 (m, 1H), 1.78–1.42 (m, 6H),1.04–0.84 (m, 18H).

EXAMPLE 1 (3)(2S)-N-[(2S)-4-methyl-1-(3-methoxymethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.67 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.35 (s, 5H), 6.59 (brd, J=6.3 Hz, 1H), 5.30 (m, 1H),5.20–5.09 (m, 5H), 4.21 (m, 1H), 3.48 (s, 3H), 1.80–1.40 (m, 6H),1.02–0.88 (m, 12H).

EXAMPLE 1 (4)(2S)-N-[(2S)-1-(3-butyl-2-oxo-1,3,4-oxadiazolin-5-yl)-4-methyl-1-oxo-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.67 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.35 (s, 5H), 6.43 (brd, J=7.2 Hz, 1H), 5.33 (m, 1H),5.18–5.05 (m, 3H), 4.20 (m, 1H), 3.84 (t, J=7.2 Hz, 2H), 1.83–1.31 (m,10H), 1.02–0.88 (m, 15H).

EXAMPLE 1 (5)(2S)-N-[(2S)-1-(3-benzyl-2-oxo-1,3,4-oxadiazolin-5-yl)-4-methyl-1-oxo-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.38 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.19 (m, 10H), 6.42 (brd, J=8.2 Hz, 1H), 5.30 (m, 1H),5.18–5.05 (m, 3H), 5.03 (d, J=15.0 Hz, 1H), 4.97 (d, J=15.0 Hz, 1H),4.19 (m, 1H), 1.80–1.40 (m, 6H), 1.00–0.88 (m, 12H).

EXAMPLE 1 (6)(2S)-N-[(2S)-4-methyl-1-oxo-1-(3-propyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.40 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 7.35 (s, 5H), 6.47 (brd, J=7.0 Hz, 1H), 5.34 (m, 1H),5.16–5.00 (m, 3H), 4.20 (m, 1H), 3.81 (t, J=6.2 Hz, 2H), 1.83 (m, 2H),1.80–1.40 (m, 6H), 1.00–0.88 (m, 15H)

EXAMPLE 1 (7)(2S)-N-[(2S)-4-methyl-1-oxo-1-(3-pentyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.47 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 7.35 (s, 5H), 6.63 and 6.43 (each brd, J=8.0 Hz, totally1H), 5.34 (m, 1H), 5.20–5.05 (m, 3H), 4.20 (m, 1H), 3.83 (m, 2H), 1.80(quintet, J=4.2 Hz, 2H), 1.73–1.30 (m, 10H), 1.00–0.88 (m, 15H).

EXAMPLE 1 (8)(2S)-N-[(2S)-4-methyl-1-(3-(1-methylethyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.75 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃) δ 7.40–7.30 (m, 5H), 6.48 (d, J=6.6 Hz, 1H) 5.42–5.32 (m,1H), 5.18–5.03 (m, 3H), 4.48–4.39 (m, 1H), 4.28–4.17 (m, 1H), 1.78–1.40(m, 6H), 1.43 (d, J=6.6 Hz, 3H), 1.42 (d, J=6.6 Hz, 3H), 1.00–0.93 (m,12H).

EXAMPLE 1 (9)(2S)-N-[(2S)-1-(3-ethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-4-methyl-1-oxo-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.48 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 7.35 (m, 5H), 6.43 (m, 1H), 5.34 (m, 1H), 5.20–5.02 (m,3H), 4.20 (m, 1H), 3.90 (q, J=7.2 Hz, 2H), 1.78–1.45 (m, 6H), 1.43 (t,J=7.2 Hz, 3H), 1.05–0.83 (m, 12H).

EXAMPLE 1 (10)(2S)-N-[(2S)-1-(3-cyclohexylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-4-methyl-1-oxo-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.36 (n-hexane:ethyl acetate=3:1);

NMR (CDCl₃): δ 7.35 (s, 5H), 6.62 and 6.46 (each brd, J=8.2 Hz, totally1H), 5.35 (m, 1H), 5.20–5.00 (m, 3H), 4.21 (m, 1H), 3.70 (dd, J=12.3,7.2 Hz, 1H), 3.65 (dd, J=12.3, 7.2 Hz, 1H), 1.97–0.90 (m, 29H).

EXAMPLE 1 (11)(2S)-N-[(2S)-1-(3-cyclohexyl-2-oxo-1,3,4-oxadiazolin-5-yl)-4-methyl-1-oxo-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.50 (n-hexane:ethyl acetate=3:1);

NMR (CDCl₃): δ 7.40–7.30 (m, 5H), 6.45 (brd, J=6.3 Hz, 1H), 5.40–5.30(m, 1H), 5.18–5.07 (m, 3H), 4.27–4.15 (m, 1H), 4.04 (tt, J=11.7, 3.9 Hz,1H), 2.00–1.83 (m, 4H), 1.80–1.20 (m, 12H), 1.00–0.90 (m, 12H).

EXAMPLE 1 (12)(2S)-N-[(2S)-4-methyl-1-oxo-1-(3-(3-phenylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.50 (n-hexane:ethyl acetate=3:1);

NMR (CDCl₃): δ 7.40–7.15 (m, 10H), 6.49 (brd, J=7.5 Hz, 1H), 5.38–5.28(m, 1H), 5.18–5.02 (m, 3H), 4.27–4.13 (m, 1H), 3.86 (t, J=7.5 Hz, 2H),2.71 (t, J=7.5 Hz, 2H), 2.15 (quintet, J=7.5 Hz, 2H), 1.75–1.45 (m, 6H),1.00–0.92 (m, 12H).

EXAMPLE 1 (13)(2S)-N-[4-methyl-1-oxo-1-(3-(2-trimethylsilylethoxymethyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.48 (n-hexane:ethyl acetate=7:3);

NMR (CDCl₃) δ 7.36 and 7.35 (each s, totally 5H), 6.67 and 6.53 (brd,J=7.8 Hz, totally 1H), 5.40–5.00 (m, 6H), 4.30–4.10 (m, 1H), 3.72 and3.71 (each t, J=8.3 Hz, totally 2H), 1.80–1.40 (m, 6H), 1.10–0.80 (m,14H), 0.02 (s, 9H).

EXAMPLE 1 (14) (2S)-N-[(2S)-4-methyl-1-oxo-1(3-phenethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.75 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.40–7.18 (m, 10H), 6.50 (brd, J=6.6 Hz, 1H), 5.29 (ddd,J=9.9, 6.6,4.5 Hz, 1H), 5.20–5.05 (m, 3H), 4.28–4.16 (m, 1H), 4.17–4.00(m, 2H), 3.11 (t, J=7.5 Hz, 2H), 1.70–1.40 (m, 6H), 1.00–0.85 (m, 12H).

EXAMPLE 1 (15)(2S)-N-[(2S)-4-methyl-1-oxo-1-(3-(thiophen-3-ylmethyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.41 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃) δ 7.40–7.25 (m, 7H), 7.11 (d, J=4.8 Hz, 1H), 6.62 and 6.45(each m, totally 1H), 5.30 (m, 1H), 5.20–4.80 (m, 5H), 4.20 (m, 1H),1.78–1.40 (m, 6H), 1.03–0.84 (m, 12H).

EXAMPLE 1 (16)(2S)-N-[(2S)-4-methyl-1-oxo-1-(3-(thiophen-2-ylmethyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.39 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 7.40–7.26 (m, 6H), 7.15 (d, J=3.3 Hz, 1H), 7.00 (dd,J=4.8, 3.3 Hz, 1H), 6.60 and 6.43 (each m, totally 1H), 5.30 (m, 1H),5.23–4.95 (m, 5H), 4.20 (m, 1H), 1.80–1.40 (m, 6H), 1.03–0.83 (m, 12H).

EXAMPLE 1 (17)(2S)-N-[(2S)-1-(3-cyclopropylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-4-methyl-1-oxo-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.75 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.40–7.30 (m, 5H), 6.52 (brd, J=6.8 Hz, 1H), 5.41–5.30(m, 1H), 5.10–5.02 (m, 3H), 4.30–4.12 (m, 1H), 3.76 (dd, J=14.6, 7.2 Hz,1H), 3.63 (dd, J=14.6, 7.2 Hz, 1H), 1.80–1.42 (m, 6H), 1.36–1.18 (m,1H), 1.03–0.82 (m, 12H), 0.70–0.60 (m, 2H), 0.48–0.38 (m, 2H).

EXAMPLE 1 (18)(2S)-N-[(2S)-4-methyl-1-oxo-1-(3-(pyridin-2-ylmethyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.70 (n-hexane:ethyl acetate=1:2);

NMR (CDCl₃) δ 8.58 (d, J=7.6 Hz, 1H), 7.72 (dt, J=1.8, 7.6 Hz, 1H),7.40–7.30 (m, 6H), 7.27 (t, J=7.6 Hz, 1H), 6.62 (brd, J=7.4 Hz, 1H),5.30–5.20 (m, 2H), 5.18 (d, J=15.0 Hz, 1H), 5.10 (d, J=15.0 Hz, 1H),5.11 (s, 2H), 4.30–4.10 (m, 1H), 1.90–1.40 (m, 6H), 0.98–0.82 (m, 12H).

EXAMPLE 1 (19)(2S)-N-[(2S)-4-methyl-1-oxo-1-(3-(pyridin-3-ylmethyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.50 (n-hexane:ethyl acetate=1:2);

NMR (CDCl₃) δ 8.69 (d, J=1.8 Hz, 1H), 8.64 (dd, J=7.8, 1.8 Hz, 1H), 7.77(dt, J=7.8, 1.8 Hz, 1H), 7.40–7.30 (m, 6H), 6.59 (brd, J=7.0 Hz, 1H),5.30–5.10 (m, 2H), 5.11 (s, 2H), 5.03 (d, J=15.4 Hz, 1H), 4.95 (d,J=15.4 Hz, 1H), 4.30–4.10 (m, 1H), 1.90–1.40 (m, 6H), 1.00–0.80 (m,12H).

EXAMPLE 1 (20)(2S)-N-[(2S)-4-methyl-1-oxo-1-(3-(pyridin-4-ylmethyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.70 (n-hexane ethyl acetate=1:1);

NMR (CDCl₃): δ 8.66 (d, J=6.0 Hz, 2H), 7.40–7.30 (m, 5H), 7.30 (d, J=6.0Hz, 2H), 6.58 (brd, J=6.3 Hz, 1H), 5.30–5.20 (m, 1H), 5.20–5.10 (m, 1H),5.13 (s, 2H), 5.02 (d, J=15.6 Hz, 1H), 4.95 (d, J=15.6 Hz, 1H),4.25–4.16 (m, 1H), 1.70–1.40 (m, 6H), 1.00–0.85 (m, 12H).

EXAMPLE 1 (21)(2S)-N-[(2S)-1-(3-cyclobutylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-4-methyl-1-oxo-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.40 (n-hexane:ethyl acetate=3:1);

NMR (CDCl₃): δ 7.40–7.30 (m, 5H), 6.53 (brd, J=7.2 Hz, 1H), 5.38–5.29(m, 1H), 5.20–5.10 (m, 1H), 5.12 (s, 2H), 4.28–4.17 (m, 1H), 3.87 (dd,J=14.1, 7.5 Hz, 1H), 3.84 (dd, J=14.1, 7.5 Hz, 1H), 2.85–2.70 (m, 1H),2.20–2.00 and 2.00–1.75 (each m, totally 6H), 1.70–1.40 (m, 6H),1.00–0.85 (m, 12H).

EXAMPLE 1 (22)(2S)-N-[(2S)-1-(3-cyclopentylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-4-methyl-1-oxo-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.55 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 7.40–7.30 (m, 5H), 6.54 (brd, J=7.2 Hz, 1H), 5.34 (ddd,J=9.6, 7.2, 3.6 Hz, 1H), 5.20–5.05 (m, 1H), 5.11 (s, 2H), 4.30–4.15 (m,1H), 3.79 (dd, J=13.8, 7.8 Hz, 1H), 3.73 (dd, J=13.8, 7.8 Hz, 1H),2.43–2.30 (m, 1H), 1.85–1.25 (m, 14H), 1.00–0.82 (m, 12H).

EXAMPLE 2 TO EXAMPLE 2 (24)

By the same procedure as described in Reference Example 11→Example 1using the compound prepared in Reference Example 10 or2-amino-4-methyl-1-[3-(2-methyl)propyl-2-oxo-(1,3,4-oxadiazolin)-5-yl]pentanolhydrochloride and a compound which corresponds toN-benzyloxycarbonyl-(L)-leucine, the compounds having the followingphysical data were obtained.

EXAMPLE 2N-[4-methyl-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-pentyl]cyclohexylcarboxamide

TLC: Rf 0.45 (n-hexane:ethyl acetate=3:1);

NMR (CDCl₃): δ 5.88 (d, J=7.8 Hz, 1H), 5.39 (m, 1H), 3.68 (dd, J=13.8,6.9 Hz, 1H), 3.62 (dd, J=13.8, 6.9 Hz, 1H), 2.12–2.10 and 1.90–1.20(each m, totally 15H), 1.00–0.96 (m, 12H).

EXAMPLE 2 (1)N-[(2S)-4-methyl-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-pentyl]benzyloxycarboxamide

TLC: Rf 0.47 (n-hexane:ethyl acetate=4:1);

NMR (CDCl₃): δ 7.35 (s, 5H), 5.21 (m, 2H), 5.10 (s, 2H), 3.65 (m, 2H),2.09 (m, 1H), 1.84–1.43 (m, 3H), 1.08–0.90 (m, 12H).

EXAMPLE 2 (2)1-[(1S,2R)-2-benzoylaminocyclohexyl]-N-[4-methyl-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.55 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.83–7.74 (m, 2H), 7.52–7.37 (m, 3H), 7.17–7.12 (m, 1H),6.23 and 6.17 (each d, each J=7.0 and 7.6 Hz, totally 1H), 5.40–5.20 (m,1H), 4.42–4.25 (m, 1H), 3.70–3.50 (m, 2H), 2.90–2.78 (m, 1H), 2.23–1.25(m, 12H), 1.00–0.82 (m, 12H).

EXAMPLE 2 (3)N-[4-methyl-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-pentyl]-4-benzyloxybenzamide

TLC: Rf 0.50 (n-hexane:ethyl acetate=3:1);

NMR (CDCl₃): δ 7.76 (d, J=8.7 Hz, 2H), 7.45–7.30 (m, 5H), 7.00 (d, J=8.7Hz, 2H), 6.57 (d, J=8.1 Hz, 1H), 5.57 (ddd, J=9.3, 8.1, 3.9 Hz, 1H),5.12 (s, 2H), 3.70 (dd, J=14.1, 7.2 Hz, 1H), 3.63 (dd, J=14.1, 7.2 Hz,1H), 2.25–2.10 (m, 1H), 1.90–1.58 (m, 3H), 1.06–0.90 (m, 12H).

EXAMPLE 2 (4)N-[4-methyl-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-pentyl]-3-benzyloxybenzamide

TLC: Rf 0.50 (n-hexane:ethyl acetate=3:1);

NMR (CDCl₃) δ 7.47–7.30 (m, 8H), 7.18–7.10 (m, 1H), 6.63 (d, J=7.8 Hz,1H), 5.58 (ddd, J=9.9, 7.8, 3.9 Hz, 1H), 5.10 (s, 2H), 3.70 (dd, J=14.1,7.2 Hz, 1H), 3.64 (dd, J=14.1, 7.2 Hz, 1H), 2.25–2.10 (m, 1H), 1.87–1.58(m, 3H), 1.05 (d, J=6.0 and 6.6 Hz, 3H), 0.99 (d, J=6.0 and 6.6 Hz, 9H).

EXAMPLE 2 (5)N-[4-methyl-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-pentyl]-2-benzyloxybenzamide

TLC: Rf 0.55 (n-hexane:ethyl acetate=3:1);

NMR (CDCl₃) δ 8.37 (d, J=6.3 Hz, 1H), 8.17 (dd, J=8.1, 1.8 Hz, 1H), 7.52(dt, J=1.8, 8.1 Hz, 1H), 7.55–7.38 (m, 5H), 7.12–7.08 (m, 2H), 5.36 (dt,J=6.3, 3.9 Hz, 1H), 5.20 (d, J=10.2 Hz, 1H), 5.16 (d, J=10.2 Hz, 1H),3.67 (dd, J=13.8, 7.2 Hz, 1H), 3.60 (dd, J=13.8, 7.2 Hz, 1H), 2.23–2.08(m, 1H), 1.50–1.10 (m, 3H), 0.96 (d, J=6.6 Hz, 3H), 0.95 (d, J=6.6 Hz,3H), 0.85 (d, J=6.3 Hz, 3H), 0.70 (d, J=6.3 Hz, 3H).

EXAMPLE 2 (6)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[4-methyl-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.75 (n-hexane:ethyl acetate=7:3);

NMR (CDCl₃): δ 7.83–7.74 (m, 2H), 7.50–7.37 (m, 3H), 7.15–7.11 (m, 1H),6.25 and 6.19 (each d, each J=7.8 Hz, totally 1H), 5.40–5.20 (m, 1H),4.42–4.27 (m, 1H), 3.75–3.53 (m, 2H), 2.90–2.79 (m, 1H), 2.22–1.38 (m,12H), 1.01–0.90 (m, 6H), 0.88 (d, J=5.8 Hz, 3H), 0.83 (d, J=6.2 Hz, 3H).

EXAMPLE 2 (7)N-[4-methyl-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-pentyl]cinnamamide

TLC: Rf 0.40 (n-hexane:ethyl acetate=3:1);

NMR (CDCl₃): δ 7.64 (d, J=15.6 Hz, 1H), 7.52–7.49 (m, 2H), 7.40–7.36 (m,3H), 6.45 (d, J=15.6 Hz, 1H), 6.13 (d, J=8.1 Hz, 1H), 5.56 (ddd, J=9.9,8.1, 4.2 Hz, 1H), 3.70 (dd, J=13.8, 7.2 Hz, 1H), 3.64 (dd, J=13.8, 7.2Hz, 1H), 2.28–2.13 (m, 1H), 1.83–1.52 (m, 3H), 1.05 (d, J=6.0 Hz, 3H),0.99 (d, J=6.9 Hz, 6H), 0.98 (d, J=6.3 Hz, 3H).

EXAMPLE 2 (8)2-methylpropoxy-N-[4-methyl-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.50 (n-hexane:ethyl acetate=3:1);

NMR (CDCl₃): δ 5.30–5.10 (m, 2H), 3.84 (d, J=6.6 Hz, 2H), 3.70 (dd,J=13.8, 7.0 Hz, 1H), 3.63 (dd, J=13.8, 7.0 Hz, 1H), 2.30–2.08 (m, 1H),2.00–1.40 (m, 4H), 1.03–0.91 (m, 18H).

EXAMPLE 2 (9)N-[4-methyl-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-pentyl]benzamide

TLC: Rf 0.40 (n-hexane:ethyl acetate=3:1);

NMR (CDCl₃): δ 7.82–7.79 (m, 2H), 7.54 (tt, J=7.2, 1.8 Hz, 1H),7.48–7.43 (m, 2H), 6.59 (d, J=7.8 Hz, 1H), 5.62 (ddd, J=9.9, 7.8, 4.2Hz, 1H), 3.70 (dd, J=13.8, 7.2 Hz, 1H), 3.64 (dd, J=13.8, 7.2 Hz, 1H),2.25–2.15 (m, 1H), 1.85–1.50 (m, 3H), 1.07 (d, J=6.0 Hz, 3H), 1.00 (d,J=6.0 Hz, 9H).

EXAMPLE 2 (10)N-[4-methyl-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-pentyl]-3-cyclopentylpropionamide

TLC: Rf 0.65 (n-hexane:ethyl acetate=7:3);

NMR (CDCl₃): δ 5.89 (d, J=8.0 Hz, 1H), 5.41 (ddd, J=10.0, 8.0, 4.0 Hz,1H), 3.69 (dd, J=14.0, 7.0 Hz, 1H), 3.63 (dd, J=14.0, 7.0 Hz, 1H),2.40–2.10 (m, 4H), 1.85–1.40 (m, 11H), 1.20–1.00 (m, 2H), 1.05–0.95 (m,12H).

EXAMPLE 2 (11)N-[4-methyl-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-pentyl]benzenesulfonamide

TLC: Rf 0.50 (n-hexane:ethyl acetate=7:3);

NMR (CDCl₃): δ 7.82–7.78 (m, 2H), 7.55 (tt, J=7.5, 1.8 Hz, 1H), 7.45 (t,J=7.5 Hz, 2H), 5.32 (d, J=10.2 Hz, 1H), 4.73 (ddd, J=10.2, 7.8, 6.6 Hz,1H), 3.66 (dd, J=14.1, 7.2 Hz, 1H), 3.62 (dd, J=14.1, 7.2 Hz, 1H),2.25–2.10 (m, 1H), 1.92–1.78 (m, 1H), 1.46–1.42 (m, 2H), 0.99 (d, J=6.6Hz, 6H), 0.91 (d, J=6.6 Hz, 3H), 0.90 (d, J=6.6 Hz, 3H).

EXAMPLE 2 (12)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[(2S)-4-methyl-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.55 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.77 (dd, J=8.2, 1.6 Hz, 2H), 7.55–7.35 (m, 3H), 7.13 (d,J=8.4 Hz, 1H), 6.18 (d, J=8.2 Hz, 1H), 5.40–5.25 (m, 1H), 4.40–4.25 (m,1H), 3.68 (dd, J=16.5, 7.0 Hz, 1H), 3.63 (dd, J=16.5, 7.0 Hz, 1H), 2.84(q, J=4.9 Hz, 1H), 2.35–1.35 (m, 12H), 0.98 (d, J=6.6 Hz, 6H), 0.88 (d,J=5.8 Hz, 3H), 0.83 (d, J=6.2 Hz, 3H).

EXAMPLE 2 (13)N-[4-methyl-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-pentyl]-2-benzoylaminobenzamide

TLC: Rf 0.37 (n-hexane:ethyl acetate=7:3);

NMR (CDCl₃): δ 11.80 (s, 1H), 8.83 (d, J=8.4 Hz, 1H), 7.99 (dd, J=7.7,1.9 Hz, 2H), 7.65–7.45 (m, 5H), 7.15 (t, J=7.7 Hz, 1H), 6.76 (d, J=7.6Hz, 1H), 5.65–5.50 (m, 1H), 3.71 (dd, J=13.9, 7.1 Hz, 1H), 3.67 (dd,J=13.9, 7.4 Hz, 1H), 2.30–2.10 (m, 1H), 1.90–1.50 (m, 3H), 1.08 (d,J=5.8 Hz, 3H), 1.05–0.95 (m, 9H).

EXAMPLE 2 (14)N-[4-methyl-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-pentyl]-1-[(2S)-N-benzoylpiperidin-2-yl]carboxamide

TLC: Rf 0.30 and 0.23 (n-hexane:ethyl acetate=7:3);

NMR (CDCl₃): δ 7.55–7.30 (m, 5H), 7.25–7.10 (m, 1H), 5.40–5.20 (m, 2H),3.80–3.45 (m, 3H), 3.10–2.90 (m, 1H), 2.35–2.10 (m, 2H), 1.90–1.40 (m,6H), 1.10–0.85 (m, 14H).

EXAMPLE 2 (15)N-[4-methyl-2-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-oxo-2-pentyl]-1-[(2S)-N-phenethylpiperidin-2-yl]carboxamide

TLC: Rf 0.71 and 0.59 (n-hexane:ethyl acetate=3:2);

NMR (CDCl₃): δ 7.40–7.10 (m, 5H), 7.03 and 6.78 (each br, totally 1H),5.30–5.10 (m, 1H), 3.66 (d, J=13.8 Hz, 1H), 3.62 and 3.61 (each d,J=13.8 Hz, totally 1H), 3.45–3.20 (m, 1H), 3.10–2.70 (m, 4H), 2.70–1.10(m, 12H), 1.05–0.80 (m, 12H).

EXAMPLE 2 (16)N-[4-methyl-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-pentyl)-1-[(2S)-N-benzylpiperidin-2-yl]carboxamide

TLC: Rf 0.56 and 0.52 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 7.45–7.15 (m, 6H), 5.45–5.30 (m, 1H), 3.98 and 3.89 (eachd, J=13.4 and 14.0 Hz, totally 1H), 3.75–3.55 (m, 2H), 3.29 and 3.17(each d, J=14.0 and 13.4 Hz, totally 1H), 3.00–2.80 (m, 2H), 2.25–1.20(m, 11H), 1.05–0.75 (m, 12H).

EXAMPLE 2 (17)N-[(2S)-4-methyl-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-pentyl]-1-[(2S)-N-phenacylpiperidin-2-yl]carboxamide

TLC: Rf 0.35 and 0.31 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 8.00–7.90 (m, 2H), 7.70–7.30 (m, 4H), 5.25–5.10 (m, 1H),4.15 and 3.98 (each d, J=18.0 Hz, totally 1H), 3.90 (d, J=18.0 Hz, 1H),3.75–3.50 (m, 2H), 3.20–3.00 (m, 2H), 2.25–1.20 (m, 1H), 1.05–0.70 (m,12H).

EXAMPLE 2 (18)N-[4-methyl-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-pentyl]-1-[(2S)-N-benzylcarbonylpiperidin-2-yl]carboxamide

TLC: Rf 0.67 and 0.61 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.40–7.20 (m, 5H), 6.58 and 6.52 (each d, J=7.4 Hz,totally 1H), 5.35–5.05 (m, 2H), 3.95–3.75 (m, 3H), 3.67 (dd, J=14.0, 6.9Hz, 1H), 3.61 (dd, J=14.0, 7.2 Hz, 1H), 3.15–2.90 (m, 1H), 2.30–2.00 (m,2H), 2.00–1.10 (m, 8H), 1.05–0.80 (m, 12H).

EXAMPLE 2 (19)N-[(2S)-4-methyl-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-pentyl]-1-[(3R)-N-benzoylpiperidin-3-yl]carboxamide

TLC: Rf 0.67 (chloroform:methanol=19:1);

NMR (CDCl₃): δ 7.50–7.30 (m, 5H), 6.97 (br, 1H), 5.34 (br, 1H),4.30–4.10 (br, 1H), 3.68 (dd, J=14.0, 7.0 Hz, 1H), 3.63 (dd, J=14.0, 7.0Hz, 1H), 3.65–3.45 (m, 2H), 3.29 (br, 1H), 2.54 (br, 1H), 2.30–1.30 (m,8H), 0.99 (d, J=6.6 Hz, 12H).

EXAMPLE 2 (20)N-[4-methyl-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-pentyl]-1-[(3R)-N-benzylpiperidin-3-yl]carboxamide

TLC: Rf 0.46 (chloroform:methanol=19:1);

NMR (CDCl₃): δ 8.84 and 8.68 (each br, totally 1H), 7.45–7.20 (m, 5H),5.42–5.26 (m, 1H), 3.75–3.35 (m, 4H), 3.10–2.70 (m, 2H), 2.60–2.45 (m,1H), 2.40–1.40 (m, 10H), 1.05–0.80 (m, 12H).

EXAMPLE 2 (21)N-[(2S)-4-methyl-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-pentyl]-1-[(2S)-N-(3-phenylpropyl)piperidin-2-yl]carboxamide

TLC: Rf 0.69 (chloroform:methanol=19:1);

NMR (CDCl₃): δ 7.40–7.10 (m, 6H), 5.45–5.30 (m, 1H), 3.68 (dd, J=13.8,7.2 Hz, 1H), 3.64 (dd, J=13.8, 7.2 Hz, 1H), 3.20–3.05 (m, 1H), 2.85–2.50(m, 4H), 2.30–1.20 (m, 14H), 1.05–0.90 (m, 12H).

EXAMPLE 2 (22)N-[(2S)-4-methyl-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-pentyl]-1-[(2S)-N-phenethylpiperidin-2-yl]carboxamide

TLC: Rf 0.62 (chloroform:methanol=97:3);

NMR (CDCl₃): δ 7.30–7.10 (m, 5H), 6.74 (d, J=7.2 Hz, 1H), 5.25–5.10 (m,1H), 3.66 (dd, J=13.9, 7.0 Hz, 1H), 3.61 (dd, J=13.9, 7.2 Hz, 1H),3.40–3.25 (m, 1H), 3.05–2.70 (m, 4H), 2.45–1.10 (m, 12H), 1.05–0.85 (m,12H).

EXAMPLE 2 (23)N-[(2S)-4-methyl-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-pentyl]-1-[(2S)-N-(4-phenylbutyl)piperidin-2-yl]carboxamide

TLC: Rf 0.57 (chloroform:methanol=49:1);

NMR (CDCl₃): δ 7.35–7.10 (m, 6H), 5.40–5.25 (m, 1H), 3.67 (dd, J=13.9,7.0 Hz, 1H), 3.63 (dd, J=13.9, 7.0 Hz, 1H), 3.15–3.00 (m, 1H), 2.80–2.40(m, 4H), 2.30–1.20 (m, 16H), 1.05–0.85 (m, 12H).

EXAMPLE 2 (24)N-[(2S)-4-methyl-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-pentyl]-1-(2-benzyloxycyclohexyl)carboxamide

TLC: Rf 0.67 (n-hexane:ethyl acetate=3:2);

NMR (CDCl₃): δ 7.70–7.50 (m, 1H), 7.45–7.30 (m, 5H), 5.30–5.15 (m, 1H),4.72 and 4.68 (each d, J=11.4 and 11.0 Hz, totally 1H), 4.55 and 4.46(each d, J=11.0 and 11.4 Hz, totally 1H), 3.95–3.80 (m, 1H), 3.75–3.50(m, 2H), 2.70–2.45 (m, 1H), 2.30–1.15 (m, 12H), 0.97, 0.88, 0.77 and0.76 (each d, J=7.0, 6.2, 6.4 and 5.8 Hz, totally 12H).

REFERENCE EXAMPLE 12(2S)-2-(N-t-butoxycarbonylamino)-4-methyl-1-(2-thioxo-1,3,4-oxadiazolin-5-yl)pentanol

To an aqueous solution of the compound prepared in Reference Example 7(3.0 g) in ethanol 95% aqueous solution (55 ml) were added potassiumhydroxide (726 mg) and carbon disulfide (662 ml) and the mixture wasstirred overnight at 90° C. The reaction solution was cooled down toroom temperature and thereto was added cold 10% aqueous solution ofcitric acid and was extracted with ethyl acetate. The organic layer waswashed with saturated aqueous solution of sodium chloride, dried overanhydrous sodium sulfate and was concentrated. The residue was purifiedby column chromatography on silica gel (ethyl acetate) and thereto wasadded 10% aqueous solution of citric acid, and was extracted with ethylacetate and the organic layer was washed with saturated aqueous solutionof sodium chloride, dried over anhydrous sodium sulfate and wasconcentrated to give the title compound (3.1 g) having the followingphysical data.

TLC: Rf 0.31 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 11.80 (br, 1H), 5.28 and 5.09 (each br, totally 1H),5.00–4.40 (m, 2H), 4.20–3.90 (m, 1H), 2.00–1.20 (m, 3H), 1.47 and 1.43(each s, totally 9H), 1.05–0.85 (m, 6H).

REFERENCE EXAMPLE 13(2S)-2-(N-t-butoxycarbonylamino)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)pentanol

To a solution of the compound prepared in Reference Example 12 (634 mg)in N,N-dimethylformamide (4 ml) was added potassium carbonate (304 mg)at room temperature and the mixture was stirred for 3 hours. To thereaction mixture was added isopropyl bromide (207 ml) and the mixturewas stirred for another 4 days. To the reaction mixture was added waterand was extracted with ethyl acetate. The organic layer was washed withwater and saturated aqueous solution of sodium chloride successively,dried over anhydrous sodium sulfate and was concentrated. The residuewas purified by column chromatography on silica gel (n-hexane:ethylacetate=4:1˜1:1) to give the title compound (603 mg) having thefollowing physical data.

TLC: Rf 0.59 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 4.95–4.75 (m, 2H), 4.61 (d, J=6.6 Hz, 0.5H), 4.20–3.80(m, 2.5H), 1.80–1.20 (m, 3H), 1.49 (d, J=6.9 Hz, 3H), 1.48 (d, J=6.6 Hz,3H), 1.45 and 1.38 (each s, totally 9H), 1.00–0.90 (m, 6H).

REFERENCE EXAMPLE 14(2S)-2-amino-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)pentanolhydrochloride

To a solution of the compound prepared in Reference Example 13 (291 mg)in ethyl acetate (3 ml) was added 4N hydrochloric acid-ethyl acetate (6ml) at 0° C. and the mixture was stirred for 30 minutes. The reactionmixture was concentrated to give a crude product having the followingphysical data of the title compound.

TLC: Rf 0.33 (chloroform:methanol=9:1).

REFERENCE EXAMPLE 15(2S)-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-hydroxy-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

To a solution of the compound prepared in Reference Example 14 inN,N-dimethylformamide (2 ml) were added N-benzyloxycarbonyl-(L)-leucine(224 mg), 1-hydroxybenzotriazole (173 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (216 mg) andN-methyl morpholine(124 ml), and the mixture was stirred for 3.5 hours.Thereto was added N,N-dimethylpropanediamine and a cold 10% aqueoussolution of citric acid, and was extracted with ethyl acetate. Theorganic layer was washed with a 10% aqueous solution of citric acid, asaturated aqueous solution of sodium bicarbonate, water and saturatedaqueous solution of sodium chloride and dried over anhydrous sodiumsulfate and was concentrated to give a crude product of the titlecompound (407 mg) having the following physical data.

TLC: Rf 0.51 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.40–7.25 (m, 5H), 6.85 and 6.66 (each d, J=9.2 and 8.0Hz, totally 1H), 5.27 (d, J=7.4 Hz, 1H), 5.15–4.00 (m, 6H), 3.95–3.75(m, 1H), 1.80–1.20 (m, 12H), 1.00–0.75 (m, 12H).

EXAMPLE 3(2S)-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

To a solution of the compound prepared in Reference Example 15 (390 mg)in methylene chloride (4 ml) was added (diacetoxyiodo)benzene (273 mg)and TEMPO reagent (2,2,6,6-tetramethyl-1-piperidinyloxy, free radical)(13 mg) at room temperature and the mixture was stirred overnight. Tothe reaction mixture was added a saturated aqueous solution of sodiumbicarbonate and was extracted with chloroform. The organic layer waswashed with saturated aqueous solution of sodium chloride, dried overanhydrous sodium sulfate and was concentrated. The residue was purifiedby column chromatography on silica gel to give the compound of thepresent invention (350 mg) having the following physical data.

TLC: Rf 0.56 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 7.35 (s, 5H), 6.63 (d, J=7.2 Hz, 1H), 5.50–5.35 (m, 1H),5.20–5.05 (m, 3H), 4.30–4.10 (m, 1H), 4.04 (septet, J=6.6 Hz, 1H),1.90–1.40 (m, 6H), 1.54 (d, J=6.6 Hz, 6H), 1.05–0.80 (m, 12H).

EXAMPLE 3 (1) TO EXAMPLE 3 (9)

By the same procedure as described in Reference Example 15→Example 3using the compound prepared in Reference Example 14 or a correspondingamide derivative and N-benzyloxycarbonyl-(L)-leucine or a correspondingcarboxylic acid derivative, the compounds of the present inventionhaving the following physical data were obtained.

EXAMPLE 3 (1)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)1-oxo-2-pentyl]carboxamide

TLC: Rf 0.61 (n-hexane ethyl acetate=1:1);

NMR (CDCl₃): δ 7.77 (dd, J=7.9, 1.7 Hz, 2H), 7.55–7.35 (m, 3H), 7.20 (d,J=8.0 Hz, 1H), 6.29 (d, J=7.6 Hz, 1H), 5.50–5.35 (m, 1H), 4.40–4.25 (m,1H), 4.04 (septet, J=6.8 Hz, 1H), 2.87 (q, J=5.0 Hz, 1H), 2.20–1.30 (m,11H), 1.54 (d, J=6.8 Hz, 1H), 0.91 (d, J=6.2 Hz, 3H), 0.85 (d, J=6.2 Hz,3H).

EXAMPLE 3 (2)(2S)-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.32 (hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 7.35 (s, 5H), 6.65 (d, J=8.4 Hz, 1H), 5.50–5.35 (m, 1H),5.20–5.02 (m, 3H), 4.30–4.15 (m, 1H), 2.79 (s, 3H), 1.90–1.40 (m, 6H),1.10–0.85 (m, 12H).

EXAMPLE 3 (3)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.47 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.85–7.70 (m, 2H), 7.55–7.35 (m, 3H), 7.19 (d, J=8.4 Hz,1H), 6.29 (d, J=7.6 Hz, 1H), 5.50–5.35 (m, 1H), 4.40–4.25 (m, 1H), 2.87(q, J=5.0 Hz, 1H), 2.79 (s, 3H), 2.20–1.40 (m, 11H), 0.91 (d, J=6.2 Hz,3H), 0.85 (d, J=6.2 Hz, 3H).

EXAMPLE 3 (4)(2S)-N-[(2S)-1-(5-benzylthio-1,3,4-oxadiazol-2-yl)-4-methyl-1-oxo-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.53 (hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 7.50–7.25 (m, 10H), 6.64 (d, J=7.4 Hz, 1H), 5.50–5.35 (m,1H), 5.20–5.00 (m, 3H), 4.55 (s, 2H), 4.30–4.15 (m, 1H), 1.90–1.40 (m,6H), 1.05–0.80 (m, 12H).

EXAMPLE 3 (5)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[(2S)-1-(5-benzylthio-1,3,4-oxadiazol-2-yl)-4-methyl-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.56 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.76 (dd, J=8.2, 1.8 Hz, 2H), 7.60–7.30 (m, 8H), 7.19 (d,J=8.0 Hz, 1H), 6.27 (d, J=7.6 Hz, 1H), 5.50–5.30 (m, 1H), 4.55 (s, 2H),4.40–4.25 (m, 1H), 2.86 (q, J=5.0 Hz, 1H), 2.20–1.30 (m, 11H), 0.90 (d,J=6.2 Hz, 3H), 0.85 (d, J=6.2 Hz, 3H).

EXAMPLE 3 (6)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[(2S)-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-hexyl]carboxamide

TLC: Rf 0.31 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃) δ 7.76 (d, J=6.9 Hz, 2H), 7.53–7.36 (m, 3H), 7.26 (brd,J=8.7 Hz, 1H), 6.39 (brd, J=8.4 Hz, 1H), 5.37 (ddd, J=8.4, 6.6, 4.8 Hz,1H), 4.33 (m, 1H), 2.83 (m, 1H), 2.80 (s, 3H), 2.20–1.18 (m, 14H), 0.77(t, J=6.9 Hz, 3H).

EXAMPLE 3 (7)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[(2S)-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-4-phenyl-2-butyl]carboxamide

TLC: Rf 0.52 (n-hexane:ethyl acetate=2:3);

NMR (CDCl₃): δ 7.77 (dd, J=8.0, 1.5 Hz, 2H), 7.55–7.00 (m, 9H), 6.41 (d,J=7.2 Hz, 1H), 5.40 (brd, J=7.7, 4.4 Hz, 1H) 4.40–4.15 (m, 1H),2.80–2.60 (m, 6H), 2.50–1.40 (m, 10H).

EXAMPLE 3 (8)(2S)-N-[(2S)-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.73 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.35 (s, 5H), 6.84 and 6.71 (each brd, J=6.6 Hz, totally1H), 5.40 (m, 1H), 5.20–5.08 (m, 3H), 4.22 (m, 1H), 2.79 (s, 3H), 2.02(m, 1H), 1.82–1.22 (m, 8H), 1.02–0.82 (m, 9H).

EXAMPLE 3 (9)(2S)-N-[(2S)-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-4-phenyl-2-butyl]-4-methyl-2-benzyloxycarbonylaminopentanamide

TLC: Rf 0.52 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.40–7.10 (m, 10H), 6.80 (brd, J=6.6 Hz, 1H), 5.42 (dt,J=7.8, 4.6 Hz, 1H), 5.20–5.00 (m, 3H), 4.30–4.10 (m, 1H), 2.78 (s, 3H),2.71 (t, J=7.5 Hz, 2H), 2.55–2.00 (m, 2H), 1.80–1.30 (m, 3H), 1.00–0.80(m, 6H).

EXAMPLE 41-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[(2S)-1-(3-cyclopropylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-4-methyl-1-oxo-2-pentyl]carboxamide

By the same procedure as described in Reference Example 11→Example 1using(2S)-2-amino-4-methyl-1-[3-cyclopropylmethyl-2-oxo-(1,3,4-oxadiazolin)-5-yl]pentanolin place of the compound prepared in Reference Example 10 and(2S,1R)-2-(benzoylamino)cyclohexylcarboxylic acid in place ofN-benzyloxycarbonyl-(L)-leucine, the compound of the present inventionhaving the following physical data was obtained.

TLC: Rf 0.53 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.77 (dd, J=7.8, 1.6 Hz, 2H), 7.55–7.35 (m, 3H), 7.13 (d,J=8.0 Hz, 1H), 6.22 (d, J=7.8 Hz, 1H), 5.45–5.30 (m, 1H), 4.40–4.25 (m,1H), 3.76 (dd, J=14.6, 7.1 Hz, 1H), 3.63 (dd, J=14.6, 7.3 Hz, 1H), 2.85(q, J=5.1 Hz, 1H), 2.20–1.10 (m, 12H), 0.89 (d, J=5.8 Hz, 3H), 0.84 (d,J=6.2 Hz, 3H), 0.70–0.35 (m, 4H).

REFERENCE EXAMPLE 162-(N-t-butoxycarbonylamino)-4-methyl-1-[3-(2-trimethylsilylethoxymethyl)-2-oxo-1,3,4-oxadiazolin-5-yl]pentanol

To a solution of the compound prepared in Reference Example 8 (6.02 g)in N,N-dimethylformamide (40 ml) was added potassium carbonate (3.04 g)at 0° C. and the mixture was stirred for 20 minutes. Thereto was addedtrimethylsilyl ethylchloromethyl ether (3.90 ml) and the mixture wasstirred for 2 hours at room temperature. Thereto was added potassiumcarbonate (3.04 g) and trimethylsilyl ethylchloromethyl ether (3.90 ml),and the mixture was stirred for another 3 hours at room temperature. Tothe reaction mixture was added ice-water and was extracted with ethylacetate. The organic layer was washed with water and saturated aqueoussolution of sodium chloride successively, dried over anhydrous sulfateand was concentrated. The residue was purified by column chromatograohyon silica gel (chloroform:methanol=1:0 to 200:1) to give the titlecompound (2.94 g) having the following physical data.

TLC: Rf 0.74 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 5.15–5.00 (m, 2H), 4.80–4.50 (m, 3H), 4.20–3.80 (m, 1H),3.67 (t, J=7.1 Hz, 2H), 1.80–1.20 (m, 3H), 1.46 and 1.42 (each s,totally 9H), 1.05–0.85 (m, 8H), 0.01 (s, 9H).

EXAMPLE 5t-butoxy-N-[4-methyl-1-oxo-1-(3-(2-trimethylsilylethoxymethyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

To a solution of oxalyl chloride (1.13 ml) in methylene chloride (26 ml)was added a solution of dimethylsulfoxide (1.84 ml) in methylenechloride (6 ml) over a period of 5 minutes at −70° C. and the mixturewas stirred for 30 minutes. Thereto was added the compound prepared inReference Example 16 (2.94 g) in methylene chloride (13 ml) over aperiod of 5 minutes and the mixture was stirred for 2 hours at −70° C.To the reaction mixture was added N-methyl morpholine (5.72 ml) and themixture was allowed to warm to −20° C. To the reaction solution wasadded 10% aqueous solution of citric acid and was extracted withmethylene chloride. The organic layer was washed with 10% aqueoussolution of citric acid, water and saturated aqueous solution of sodiumchloride successively, dried over anhydrous sodium sulfate and wasconcentrated. The residue was purified by column chromatography onsilica gel (n-hexane:ethyl acetate=6:1) to give the compound of thepresent invention (1.17 g) having the following physical data.

TLC: Rf 0.57 (n-hexane:ethyl acetate=7:3);

NMR (CDCl₃): δ 5.23 (d, J=11.6 Hz, 1H), 5.18 (d, J=11.6 Hz, 1H),5.15–4.90 (m, 2H), 3.75–3.65 (m, 2H), 1.90–1.40 (m, 3H), 1.43 (s, 9H),1.02 (d, J=6.4 Hz, 3H), 1.02–0.90 (m, 2H), 0.97 (d, J=6.6 Hz, 3H), 0.02(s, 9H).

EXAMPLE 6(2S)-2-amino-4-methyl-1-[3-(2-trimethylsilylethoxymethyl)-2-oxo-1,3,4-oxadiazolin-5-yl]pentanoneHydrochloride

To a solution of the compound prepared in Example 5 (215 mg) in ethylacetate (2 ml) was added 4N hydrochloric acid-ethyl acetate (4 ml) at 0°C. and the mixture was stirred for 1 hour. The reaction mixture wasconcentrated to give thr crude product of the compound of the presentinvention having the following physical data.

TLC: Rf 0.48 (chloroform:methanol=9:1).

EXAMPLE 71-[(1S,2R)-2-benzoylaminocyclohexyl]-N-[4-methyl-1-oxo-1-(3-(2-trimethylsilylethoxymethyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

To a solution of the compound prepared in Example 6 in methylenechloride (2 ml) were added (+)-2-benzamidocyclohexanecarbonylchloride(which was prepared from (+)-2-benzamidocyclohexanecarboxylic acid((2R,1S)-2-(benzoylamino)cyclohexanoic acid) (148 mg) and oxalylchloride (61 μl)) and N-methyl morpholine (110 μl) and the mixture wasstirred for 3 hours. To the reaction mixture was addedN,N-dimethylpropandiamine and a cold 10% aqueous solution of citric acidand was extracted with ethytl acetate. The organic layer was washed witha 10% aqueous solution of citric acid, a saturated aqueous solution ofsodium bicarbonate, water and saturated aqueous solution of sodiumchloride successively, dried over anhydrous sodium sulfate and wasconcentrated. The residue was purified by column chromatography onsilica gel (n-hexane:ethyl acetate=7:3) to give the compound of thepresent invention (120 mg) having the following physical data.

TLC: Rf 0.33 (n-hexane:ethyl acetate=7:3).

EXAMPLE 81-[(1S,2R)-2-benzoylaminocyclohexyl]-N-[1-(3-hydroxymethyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-4-methyl-1-oxo-2-pentyl]carboxamide

To a solution of the compound prepared in Example 7 (110 mg) inmethylene chloride (4 ml) was added trifluoroacetic acid (2 ml) and themixture was stirred for 2 hours at room temperature. The reactionmixture was concentrated and the residue was purified by columnchromatography on silica gel (chloroform:methanol=100:1) to give thecompound of the present invention (53 mg) having the following physicaldata.

TLC: Rf 0.46 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.80–7.65 (m, 2H), 7.60–7.35 (m, 3H), 7.07 and 6.96 (eachd, J=7.2 Hz, totally 1H), 6.55–6.30 (m, 1H), 5.31 and 5.25 (each d,J=11.4 Hz, totally 1H), 5.15 (d, J=11.4 Hz, 1H), 5.10–4.90 (m, 1H),4.40–4.25 (m, 1H), 2.83 (q, J=4.9 Hz, 1H), 2.15–1.30 (m, 1H), 1.00–0.80(m, 6H).

EXAMPLE 9 TO EXAMPLE 9 (5)

By the same procedure as described in Reference Example 11→Example 1using an amine derivative corresponding to the compound prepared inReference Example 10 and a carboxylic acid derivative corresponding toN-benzyloxycarbonyl-(L)-leucine, the compound of the present inventionhaving the following physical data were obtained.

EXAMPLE 91-[(1S,2R)-2-benzoylaminocyclohexyl]-N-[(2S)-3-methyl-1-(3-methyl-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-butyl]carboxamide

TLC: Rf 0.37 (chloroform:methanol=20:1);

NMR (CDCl₃): δ 7.77 (d, J=8.0 Hz, 2H), 7.51–7.39 (m, 3H), 7.17 (d, J=7.0Hz, 1H), 6.23 (d, J=8.4 Hz, 1H), 5.24 (dd, J=8.4, 5.0 Hz, 1H), 4.36–4.30(m, 1H), 3.55 (s, 3H), 2.84 (dt, J=5.0, 5.5 Hz, 1H), 2.27–2.18 (m, 1H),2.10–2.03 and 1.95–1.80 (each m, totally 3H), 1.70–1.65 and 1.52–1.50(each m, totally 5H), 0.95 (d, J=7.0 Hz, 3H), 0.83 (d, J=7.0 Hz, 3H).

EXAMPLE 9 (1)1-[(1S,2R)-2-benzoylaminocyclohexyl]-N-[(2S)-1-(3-butyl-2-oxo-1,3,4-oxadiazolin-5-yl)-3-methyl-1-oxo-2-butyl]carboxamide

TLC: Rf 0.49 (chloroform:methanol=20:1);

NMR (CDCl₃): δ 7.76 (d, J=7.5 Hz, 2H), 7.51–7.39 (m, 3H), 7.19 (d, J=8.0Hz, 1H), 6.24 (d, J=8.5 Hz, 1H), 5.27 (dd, J=8.5, 5.0 Hz, 1H), 4.38–4.31(m, 1H), 3.84 (t, J=7.5 Hz, 2H), 2.84 (dt, J=6.0, 4.7 Hz, 1H), 2.28–2.18(m, 1H), 2.10–2.04 and 1.95–1.66 (each m, totally 5H), 1.54–1.32 (m,7H), 0.97 (t, J=7.5 Hz, 3H), 0.94 (d, J=7.0 Hz, 3H), 0.82 (d, J=7.0 Hz,3H).

EXAMPLE 9 (2)1-[(1S,2R)-2-benzoylaminocyclohexyl]-N-[(2S)-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-hexyl]carboxamide

TLC: Rf 0.49 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.79 (m, 2H), 7.52–7.38 (m, 3H), 7.19 (brd, J=7.8 Hz,1H), 6.28 (brd, J=7.5 Hz, 1H), 5.27 (m, 1H), 4.33 (m, 1H), 3.67 (dd,J=13.8, 7.2 Hz, 1H), 3.62 (dd, J=13.8, 7.2 Hz, 1H), 2.83 (m, 1H),2.22–1.05 (m, 15H), 0.98 (m, 6H), 0.77 (m, 3H).

EXAMPLE 9 (3)1-[(1S,2R)-2-benzoylaminocyclohexyl]-N-[(2S)-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-4-phenyl-2-butyl]carboxamide

TLC: Rf 0.41 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.77 (dd, J=7.8, 1.6 Hz, 2H), 7.55–7.30 (m, 3H),7.30–7.10 (m, 4H), 7.10–7.00 (m, 2H), 6.34 (d, J=7.4 Hz, 1H), 5.31 (dt,J=4.4, 8.0 Hz, 1H), 4.45–4.25 (m, 1H), 3.61 (d, J=7.2 Hz, 2H), 2.76 (q,J=4.9 Hz), 2.63 (t, J=7.3 Hz, 2H), 2.15–1.30 (m, 11H), 0.97 (d, J=7.0Hz, 6H).

EXAMPLE 9 (4)(2S)-N-[(2S)-1(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.32 (n-hexane:ethyl acetate=3:1);

NMR (CDCl₃) δ 7.35 (s, 5H), 6.58 (brd, J=7.8 Hz, 1H), 5.30 (dt, J=4.8,7.8 Hz, 1H), 5.13 (m, 3H), 4.22 (m, 1H), 3.68 (dd, J=13.8, 7.2 Hz, 1H),3.63 (dd, J=13.8, 7.2 Hz, 1H), 2.19 (m, 1H), 2.00–1.23 (m, 9H),1.00–0.85 (m, 15H).

EXAMPLE 9 (5)(2S)-N-[(2S)-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-4-phenyl-2-butyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.43 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 7.40–7.10 (m, 10H), 6.65 (d, J=5.8 Hz, 1H), 5.34 (dt,J=4.4, 8.0 Hz, 1H), 5.12 (s, 2H), 5.04 (d, J=7.4 Hz, 1H), 4.30–4.10 (m,1H), 2.68 (t, J=7.3 Hz, 2H), 2.40–1.90 (m, 3H), 1.80–1.30 (m, 3H),1.05–0.80 (m, 12H).

EXAMPLE 10 TO EXAMPLE 10 (104)

By the same procedure as described in Reference Example 11→Example 1using the compound prepared in Reference Example 10 or a correspondingamine derivative and a corresponding carboxylic acid derivative in placeof N-benzyloxycarbonyl-(L)-leucine, and optionally converting theproduct to hydrochloride by known methods, the compound of the presentinvention having the following physical data were obtained.

EXAMPLE 101-[(1R,2S)-2-(4-nitrobenzoylamino)cyclohexyl]-N-[4-methyl-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.48 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 8.27 (d, J=9.0 Hz, 2H), 7.97 and 7.94 (each d, J=9.0 Hz,totally 2H), 7.60 and 7.46 (each d, J=7.5 Hz, totally 1H), 6.13 (brd,J=7.5 Hz, 1H), 5.41–5.26 (m, 1H), 4.30 (m, 1H), 3.66 (m, 2H), 2.83 (m,1H), 2.30–1.40 (m, 12H), 1.10–0.90 (m, 12H).

EXAMPLE 10 (1)1-[(1R,2S)-2-(4-methoxybenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.35 (n-hexane ethyl acetate=1:1);

NMR (CDCl₃): δ 7.73 (d, J=8.7 Hz, 2H), 7.01 (brd, J=7.8 Hz, 1H), 6.92(d, J=8.7 Hz, 2H), 6.24 (brd, J=7.8 Hz, 1H), 5.33 (m, 1H), 4.33 (m, 1H),3.85 (s, 3H), 3.68 and 3.61 (each dd, J=14.1, 7.2 Hz, each 1H), 2.81 (m,1H), 2.23–1.40 (m, 12H), 0.98, 0.87 and 0.82 (each d, J=6.6 Hz, totally12H).

EXAMPLE 10 (2)1-[(1R,2S)-2-(naphthalen-2-ylcarbonylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.49 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 8.25 (s, 1H), 8.00–7.80 (m, 4H), 7.60–7.50 (m, 2H), 7.23(m, 1H), 6.18 (brd, J=8.1 Hz, 1H), 5.38 (m, 1H), 4.40 (m, 1H), 3.67 and3.61 (each dd, J=13.8, 7.2 Hz, each 1H), 2.90 (m, 1H), 2.22–1.40 (m,12H), 0.97, 0.84 and 0.80 (each d, J=6.6 Hz, totally 12H).

EXAMPLE 10 (3)1-[(1R,2S)-2-(quinoxalin-2-ylcarbonylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.41 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 9.65 (s, 1H), 8.58 (brd, J=8.4 Hz, 1H), 8.23–8.10 (m,2H), 7.90–7.80 (m, 2H), 6.20 (brd, J=8.1 Hz, 1H), 5.31 (m, 1H), 4.43 (m,1H), 3.66 and 3.59 (each dd, J=14.1, 7.2 Hz, each 1H), 2.90 (m, 1H),2.22–1.40 (m, 12H), 0.99, 0.76 and 0.68 (each d, J=6.3 Hz, totally 12H).

EXAMPLE 10 (4)1-[(1R,2S)-2-(4-chlorobenzoylamino)cyclohexyl]-N-[4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.47 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃) δ 7.74 and 7.71 (each d, J=8.4 Hz, totally 2H), 7.40 (d,J=8.4 Hz, 2H), 7.23 and 7.18 (each brd, J=8.0 Hz, totally 1H), 6.20 and6.18 (each brd, J=7.8 Hz, totally 1H), 5.40–5.23 (m, 1H), 4.30 (m, 1H),3.65 (m, 2H), 2.82 (m, 1H), 2.23–1.40 (m, 12H), 1.05–0.84 (m, 12H).

EXAMPLE 10 (5)1-[(1R,2S)-2-(benzo[b]thiophen-2-ylcarbonylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(1-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.55 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.88–7.79 (m, 2H), 7.73 (s, 1H), 7.50–7.35 (m, 2H), 7.24(m, 1H), 6.30 (brd, J=8.4 Hz, 1H), 5.38 (m, 1H), 4.40–4.30 (m, 1H), 3.68and 3.61 (each dd, J=14.1, 7.2 Hz, each 1H), 2.88 (m, 1H), 2.22–1.40 (m,12H), 0.99, 0.76 and 0.68 (each d, J=6.3 Hz, totally 12H).

EXAMPLE 10 (6)1-[(1R,2S)-2-(4-fluorobenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.50 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.77 (dd, J=9.0, 5.4 Hz, 2H), 7.18 (brd, J=8.1 Hz, 1H),7.10 (t, J=9.0 Hz, 2H), 6.19 (brd, J=7.8 Hz, 1H), 5.30 (m, 1H), 4.30 (m,1H), 3.68 and 3.62 (each dd, J=13.87.2 Hz, each 1H), 2.82 (m, 1H),2.25–1.40 (m, 12H), 0.98, 0.87 and 0.84 (each d, J=6.0 Hz, totally 12H).

EXAMPLE 10 (7)1-[(1R,2S)-2-(4-t-butylbenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(1-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.54 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.68 (d, J=8.7 Hz, 2H), 7.42 (d, J=8.7 Hz, 2H), 7.05(brd, J=8.4 Hz, 1H), 6.21 (brd, J=7.5 Hz, 1H), 5.33 (m, 1H), 4.31 (m,1H), 3.67 and 3.60 (each dd, J=13.8, 7.2 Hz, each 1H), 2.83 (m, 1H),2.23–1.40 (m, 12H), 1.32 (s, 9H), 0.97, 0.86 and 0.81 (each d, J=6.0 Hz,totally 12H).

EXAMPLE 10 (8)1-[(1R,2S)-2-(pyridin-2-ylcarbonylamino)cyclohexyl]-N-[4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.34 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 8.70–8.50 (m, 2H), 8.16 (m, 1H), 7.82 (m, 1H) 7.43 (m,1H), 6.63 and 6.33 (each brd, J=7.5 Hz, totally 1H), 5.29 (m, 1H), 4.45(m, 1H), 3.62 (m, 2H), 2.80 (m, 1H), 2.23–1.40 (m, 12H), 1.05–0.90 (m,9H), 0.92 and 0.78 (each d, J=6.3 Hz, totally 3H).

EXAMPLE 10 (9)1-[(1R,2S)-2-(naphthalen-1-ylmethylcarbonylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.39 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 8.00–7.80 (m, 3H), 7.58–7.35 (m, 4H), 6.25 (brd, J=8.1Hz, 1H), 6.10 (brd, J=7.2 Hz, 1H), 5.15 (m, 1H), 4.18 (m, 1H), 4.03 and3.92 (each d, J=15.9 Hz, each 1H), 3.70 and 3.63 (each dd, J=13.8, 7.2Hz, each 1H), 2.50 (m, 1H), 2.20 (m, 1H), 1.80–0.90 (m, 23H).

EXAMPLE 10 (10)1-[(1R,2S)-2-(2-fluorobenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.50 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 8.04 (dt, J=1.8, 7.8 Hz, 1H), 7.52–7.40 (m, 2H), 7.25(brd, J=7.8 Hz, 1H), 7.11 (dd, J=11.7, 7.8 Hz, 1H), 6.24 (brd, J=7.5 Hz,1H), 5.32 (m, 1H), 4.43 (m, 1H), 3.67 and 3.60 (each dd, J=13.5, 6.9 Hz,each 1H), 2.83 (m, 1H), 2.24–1.40 (m, 12H), 0.97, 0.90 and 0.84 (each d,J=6.6 Hz, totally 12H).

EXAMPLE 10 (11)1-[(1R,2S)-2-(4-phenylbenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.50 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.84 (d, J=8.7 Hz, 2H), 7.70–7.55 (m, 4H), 7.50–7.30 (m,3H), 7.18 (brd, J=7.8 Hz, 1H), 6.18 (brd, J=7.5 Hz, 1H), 5.38 (m, 1H),4.38 (m, 1H), 3.68 and 3.61 (each dd, J=13.5, 6.9 Hz, each 1H), 2.83 (m,1H), 2.24–1.42 (m, 12H), 0.98, 0.86 and 0.84 (each d, J=6.3 Hz, totally12H).

EXAMPLE 10 (12)1-[(1R,2S)-2-(2-chloropyridin-5-ylcarbonylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.45 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 8.78 (d, J=2.7 Hz, 1H), 8.04 (dd, J=8.4, 2.7 Hz, 1H),7.55 (brd, J=8.1 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 6.10 (brd, J=7.5 Hz,1H), 5.38 (m, 1H), 4.28 (m, 1H), 3.70 and 3.64 (each dd, J=13.5, 6.9 Hz,each 1H), 2.82 (m, 1H), 2.20 (m, 1H), 2.10–1.40 (m, 11H), 1.00, 0.93 and0.90 (each d, J=6.3 Hz, totally 12H).

EXAMPLE 10 (13)1-[(1R,2S)-2-(2-methylthiopyridin-3-ylcarbonylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.40 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 8.50 (dd, J=7.2, 1.5 Hz, 1H), 7.74 (dd, J=7.5, 1.5 Hz,1H), 7.14 (brd, J=8.1 Hz, 1H), 7.03 (dd, J=7.5, 7.2 Hz, 1H), 6.17 (brd,J=7.5 Hz, 1H), 5.30 (m, 1H), 4.39 (m, 1H), 3.67 and 3.60 (each dd,J=13.8, 7.2 Hz, each 1H), 2.82 (m, 1H), 2.56 (s, 3H), 2.23–1.40 (m,12H), 1.13, 0.97, 0.90, and 0.88 (each d, J=6.3 Hz, each 3H).

EXAMPLE 10 (14)1-[(1R,2S)-2-(4-cyanobenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.48 (n-hexane ethyl acetate=1:1);

NMR (CDCl₃): δ 7.87 (d, J=8.6 Hz, 2H), 7.73 (d, J=8.6 Hz, 2H), 7.53(brd, J=8.0 Hz, 1H), 6.12 (brd, J=7.5 Hz, 1H), 5.38 (m, 1H), 4.30 (m,1H), 3.71 and 3.62 (each dd, J=14.0, 7.4 Hz, each 1H), 2.82 (m, 1H),2.30–1.40 (m, 12H), 1.04–0.88 (m, 12H).

EXAMPLE 10 (15)1-[(1R,2S)-2-(4-dimethylaminobenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.57 (chloroform methanol=9:1);

NMR (CDCl₃): δ 7.65 (d, J=9.0 Hz, 2H), 6.81 (brd, J=7.8 Hz, 1H), 6.66(d, J=9.0 Hz, 2H), 6.32 (brd, J=7.2 Hz, 1H), 5.30 (m, 1H), 4.38 (m, 1H),3.67 and 3.60 (each dd, J=13.8, 7.2 Hz, each 1H), 3.02 (s, 6H), 2.82 (m,1H), 2.23–2.00 (m, 2H), 1.88 (m, 2H), 1.80–1.40 (m, 8H), 0.98 (d, J=6.9Hz, 6H), 0.86 and 0.82 (each d, J=5.7 Hz, each 3H).

EXAMPLE 10 (16)[(2S)-N-phenethylpyrrolidin-2-yl]-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.52 (HPTLC, chloroform:methanol=100:1);

NMR (CDCl₃): δ 7.48 and 7.38 (each brd, J=8.4 Hz, totally 1H), 7.35–7.17(m, 5H), 5.23–5.12 (m, 1H), 3.66 and 3.60 (each dd, J=13.8, 7.2 Hz, each1H), 3.43–3.32 (m, 1H), 3.15–2.99 (m, 1H), 2.93–2.65 (m, 4H), 2.45–2.31(m, 1H), 2.30–2.10 (m, 2H), 1.90–1.62 (m, 4H), 1.62–1.10 (m, 2H),1.05–0.90 (m, 12H).

EXAMPLE 10 (17)[(2S)-N-(3-phenylpropyl)pyrrolidin-2-yl]-N-[1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.48 and 0.40 (HPTLC, chloroform:methanol=100:1);

NMR (CDCl₃): δ 7.93 and 7.82 (each brd, J=9.3 Hz, totally 1H), 7.32–7.12(m, 5H), 5.42–5.25 (m, 1H), 3.72–3.53 (m, 2H), 3.25–3.19 (m, 1H),3.08–3.04 (m, 1H), 2.82–2.42 (m, 4H), 2.40–2.13 (m, 1H), 2.13–2.08 (m,2H), 1.90–1.42 (m, 8H), 1.05–0.83 (m, 12H).

EXAMPLE 10 (18)[(2R)-N-phenethylpyrrolidin-2-yl]-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.56 (HPTLC, chloroform:methanol=100:1);

NMR (CDCl₃): δ 7.53 and 7.37 (each brd, J=7.8 Hz, totally 1H), 7.27–7.15(m, 5H), 5.23–5.13 (m, 1H), 3.66 and 3.60 (each dd, J=13.8, 7.2 Hz, each1H), 3.43–3.32 (m, 1H), 3.15–2.99 (m, 1H), 2.95–2.65 (m, 4H), 2.50–2.32(m, 1H), 2.30–2.10 (m, 2H), 1.90–1.73 (m, 4H), 1.60–1.10 (m, 2H),1.05–0.90 (m, 12H).

EXAMPLE 10 (19)1-[(1R,2S)-2-(4-dimethylaminomethylbenzoylamino)cyclohexyl]-N-[4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.49 and 0.40 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.76 and 7.72 (each d, J=8.0 Hz, totally 2H), 7.37 and7.36 (each d, J=8.0 Hz, totally 2H), 7.20–7.05 (m, 1H), 6.34 and 6.26(each d, J=7.0 and 7.6 Hz, totally 1H), 5.40–5.20 (m, 1H), 4.45–4.25 (m,1H), 3.75–3.50 (m, 2H), 3.46 (s, 2H), 2.90–2.80 (m, 1H), 2.24 (s, 6H),2.20–1.35 (m, 12H), 1.05–0.80 (m, 12H).

EXAMPLE 10 (20)piperidino-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.50 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 5.23 (ddd, J=9.6, 7.8 and 4.2 Hz, 1H), 4.82 (d, J=7.8 Hz,1H), 3.68 and 3.61 (each dd, J=13.8 and 7.2 Hz, each 1H), 3.43–3.26 (m,4H), 2.27–2.08 (m, 1H), 1.88–1.38 (m, 9H), 1.03–0.95 (m, 12H).

EXAMPLE 10 (21)[(2R)-2-phenylaminocarbonylpiperidino]-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.56 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 8.05 (brs, 1H), 7.54 (d, J=7.2 Hz, 2H), 7.32 (t, J=7.2Hz, 2H), 7.09 (t, J=7.2 Hz, 1H), 5.25 (ddd, J=9.9, 7.2 and 3.9 Hz, 1H),5.07–4.96 (m, 2H), 3.74–3.54 (m, 3H), 3.15 (td, J=12.6 and 2.4 Hz, 1H),2.45–2.32 (m, 1H), 2.26–2.09 (m, 1H), 1.90–1.42 (m, 8H), 1.10–0.92 (m,12H).

EXAMPLE 10 (22)1-[(1R,2S)-2-benzoylaminocyclopentyl]-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.28 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.81–7.74 (m, 2H), 7.53–7.38 (m, 3H), 6.89 (brd, J=7.8Hz, 1H), 6.13 (d, J=7.5 Hz, 1H), 5.33–5.21 (m, 1H), 4.71–4.58 (m, 1H),3.67 (dd, J=13.5, 7.2 Hz, 1H), 3.61 (dd, J=13.5, 7.2 Hz, 1H), 3.05 (q,J=7.5 Hz, 1H), 2.24–1.30 (m, 10H), 0.98 (d, J=6.9 Hz, 6H), 0.70 and 0.69(each d, J=6.0 Hz, totally 6H).

EXAMPLE 10 (23)1-[(1R,2S)-2-(4-dimethylaminomethyl-2-fluorobenzoylamino)cyclohexyl]-N-[4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.73 and 0.55 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 8.01–7.90 (m, 1H), 7.45–7.32 (m, 1H), 7.20–7.08 (m, 2H),6.42 and 6.24 (each brd, J=6.3 Hz, totally 1H), 5.38–5.25 (m, 1H),4.51–4.40 (m, 1H), 3.70–3.50 (m, 2H), 3.46 (s, 2H), 2.84–2.70 (m, 1H),2.25 (s, 6H), 2.20–1.40 (m, 12H), 1.02–0.80 (m, 12H).

EXAMPLE 10 (24)1-[(1R,2S)-2-(3-dimethylaminomethylbenzoylamino)cyclohexyl]-N-[4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.48 and 0.46 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.75–7.60 (m, 2H), 7.50–7.30 (m, 2H), 7.10 (d, J=8.0 Hz,1H), 6.29 and 6.24 (each d, J=8.2 Hz, totally 1H), 5.40–5.20 (m, 1H),4.45–4.25 (m, 1H), 3.67 and 3.66 (each dd, J=14.0, 7.1 Hz, totally 1H),3.63 and 3.60 (each dd, J=14.0, 7.1 Hz, totally 1H), 3.47 (s, 2H),2.90–2.80 (m, 1H), 2.25 and 2.24 (each s, totally 6H), 2.20–1.35 (m,12H), 1.05–0.80 (m, 12H).

EXAMPLE 10 (25)1-[(1S,2R)-2-benzoylaminocyclopentyl]-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.33 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.83–7.75 (m, 2H), 7.52–7.37 (m, 3H), 6.91 (brd, J=8.1Hz, 1H), 6.23 (brd, J=5.7 Hz, 1H), 5.22–5.12 (m, 1H), 4.68–4.54 (m, 1H),3.65 (dd, J=14.1, 7.2 Hz, 1H), 3.56 (dd, J=14.1, 7.2 Hz, 1H), 3.13–3.03(m, 1H), 2.22–1.30 (m, 10H), 0.97 and 0.96 (each d, J=6.6 Hz, totally6H), 0.94 and 0.91 (each d, J=6.6 Hz, totally 6H).

EXAMPLE 10 (26) 1-[(1R,2S)-2-(2-dimethylaminomethylbenzoylamino)cyclohexyl]-N-[4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.41 and 0.37 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 10.65–10.45 (m, 1H), 8.05–7.90 (m, 1H), 7.45–7.30 (m,2H), 7.25–7.10 (m, 1H), 7.01 and 6.36 (each d, J=7.0 and 7.4 Hz, totally1H), 5.25–5.10 (m, 1H), 4.51 and 4.34 (each br, totally 1H), 3.80–3.30(m, 4H), 3.10–2.90 (m, 1H), 2.23 and 2.20 (each s, totally 6H),2.20–1.20 (m, 12H), 1.05–0.75 (m, 12H).

EXAMPLE 10 (27)1-[(1R,2S)-2-(4-methylbenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.43 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.68 (d, J=8.4 Hz, 2H), 7.21 (d, J=8.4 Hz, 2H), 7.04(brd, J=8.1 Hz, 1H), 6.16 (brd, J=7.2 Hz, 1H), 5.40–5.30 (m, 1H),4.40–4.30 (m, 1H), 3.68 and 3.61 (each dd, J=13.8, 6.9 Hz, each 1H),2.88–2.79 (m, 1H), 2.39 (s, 3H), 2.25–1.40 (m, 12H), 0.98, 0.87 and 0.82(each d, J=6.3 Hz, totally 12H).

EXAMPLE 10 (28)1-[(1R,2S)-2-(3-methylbenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.42 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.59 (s, 1H), 7.55 (t, J=6.0 Hz, 1H), 7.30 (d, J=6.0 Hz,2H), 7.05 (brd, J=8.1 Hz, 1H), 6.14 (brd, J=7.5 Hz, 1H), 5.40–5.30 (m,1H), 4.40–4.30 (m, 1H), 3.68 and 3.61 (each dd, J=13.8, 6.9 Hz, each1H), 2.88–2.80 (m, 1H), 2.40 (s, 3H), 2.24–1.40 (m, 12H), 0.98, 0.87 and0.82 (each d, J=6.3 Hz, totally 12H).

EXAMPLE 10 (29)1-[(1R,2S)-2-(2-methylbenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.44 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.38–7.16 (m, 4H), 6.66 (brd, J=8.7 Hz, 1H), 6.13 (brd,J=8.1 Hz, 1H), 5.40–5.30 (m, 1H), 4.40–4.30 (m, 1H), 3.68 and 3.61 (eachdd, J=13.8, 6.9 Hz, each 1H), 2.90–2.82 (m, 1H), 2.43 (s, 3H), 2.30–1.40(m, 12H), 1.04–0.90 (m, 12H).

EXAMPLE 10 (30)1-[(1R,2S)-2-(3-chlorobenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.53 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.76 (t, J=1.8 Hz, 1H), 7.62 (d, J=7.5 Hz, 1H), 7.47 (dt,J=7.5, 1.8 Hz, 1H), 7.36 (t, J=7.5 Hz, 1H), 7.20 (brd, J=8.1 Hz, 1H),6.10 (brd, J=8.1 Hz, 1H), 5.42–5.30 (m, 1H), 4.38–4.25 (m, 1H), 3.69 and3.62 (each dd, J=14.1, 7.2 Hz, each 1H), 2.88–2.80 (m, 1H), 2.30–1.40(m, 12H), 0.99, 0.89 and 0.86 (each d, J=6.0 Hz, totally 12H).

EXAMPLE 10 (31)1-[(1R,2S)-2-(2-chlorobenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.41 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.60 (dd, J=6.9, 2.4 Hz, 1H), 7.42–7.25 (m, 3H), 6.99(brd, J=8.4 Hz, 1H), 6.14 (brd, J=7.8 Hz, 1H), 5.38–5.25 (m, 1H),4.43–4.35 (m, 1H), 3.68 and 3.61 (each dd, J=13.8, 7.2 Hz, each 1H),2.88–2.78 (m, 1H), 2.23–1.41 (m, 12H), 1.05–0.88 (m, 12H).

EXAMPLE 10 (32)1-[(1R,2S)-2-(3-fluorobenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.49 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.50 (m, 2H), 7.40 (m, 1H), 7.30–7.15 (m, 2H), 6.10 (brd,J=8.4 Hz, 1H), 5.42–5.31 (m, 1H), 4.38–4.26 (m, 1H), 3.68 and 3.61 (eachdd, J=13.8, 7.2 Hz, each 1H), 2.85–2.80 (m, 1H), 2.30–1.40 (m, 12H),0.98, 0.88, and 0.86 (each d, J=6.6 Hz, totally 12H).

EXAMPLE 10 (33)1-[(1R,2S)-2-(2-methoxybenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.36 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 8.55 (brd, J=8.1 Hz, 1H), 8.18 (dd, J=7.8, 1.8 Hz, 1H),7.46 (dt, J=1.8, 7.8 Hz, 1H), 7.08 (t, J=7.8 Hz, 1H), 6.97 (d, J=7.8 Hz,1H), 6.58 (brd, J=7.8 Hz, 1H), 5.30–5.20 (m, 1H), 4.65–4.50 (m, 1H),3.99 (s, 3H), 3.68 and 3.61 (each dd, J=13.8, 7.8 Hz, each 1H),2.80–2.70 (m, 1H), 2.25–1.38 (m, 12H), 0.96, 0.78, and 0.74 (each d,J=6.3 Hz, totally 12H).

EXAMPLE 10 (34)1-[(1R,2S)-2-(3-methoxybenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.37 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.40–7.30 (m, 3H), 7.11 (brd, J=7.8 Hz, 1H), 7.02 (m,1H), 6.14 (brd, J=7.8 Hz, 1H), 5.40–5.30 (m, 1H), 4.40–4.30 (m, 1H),3.85 (s, 3H), 3.68 and 3.61 (each dd, J=13.8, 7.8 Hz, each 1H),2.88–2.80 (m, 1H), 2.30–1.40 (m, 12H), 0.98, 0.90, and 0.88 (each d,J=6.3 Hz, totally 12H).

EXAMPLE 10 (35)1-[(1R,2R)-2-benzoylaminocyclopentyl]-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.34 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 8.57 (brd, J=6.0 Hz, 1H), 7.82–7.73 (m, 2H), 7.58–7.42(m, 3H), 6.27 (brd, J=6.0 Hz, 1H), 5.30–5.20 (m, 1H), 4.45–4.35 (m, 1H),3.67 (dd, J=13.8, 7.2 Hz, 1H), 3.60 (dd, J=13.8, 7.2 Hz, 1H), 2.94–2.79(m, 1H), 2.27–1.50 (m, 10H), 1.08–0.91 (m, 12H).

EXAMPLE 10 (36)1-[(1S,2S)-2-benzoylaminocyclopentyl]-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.28 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 8.84 (brd, J=6.0 Hz, 1H), 7.77 (d, J=7.2 Hz, 2H),7.58–7.42 (m, 3H), 6.26 (brd, J=5.7 Hz, 1H), 5.29–5.20 (m, 1H),4.52–4.43 (m, 1H), 3.67 (dd, J=13.8, 7.2 Hz, 1H), 3.61 (dd, J=13.8, 7.2Hz, 1H), 2.93–2.84 (m, 1H), 2.29–1.48 (m, 10H), 1.02 and 1.00 (each d,J=6.6 Hz, totally 6H), 0.98 (d, J=6.6 Hz, 6H).

EXAMPLE 10 (37)1-[(1R,2S)-2-(4-dimethylaminomethyl-3-fluorobenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamideHydrochloride

TLC: Rf 0.32 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 8.47 and 8.37 (each brd, J=6.9 Hz, totally 1H), 8.03and 7.88 (each brd, J=7.8 Hz, totally 1H), 7.80–7.58 (m, 3H), 4.90 (m,1H), 4.42–4.25 (m, 3H), 3.56 and 3.51 (each dd, J=12.3, 6.9 Hz, each1H), 2.74 (brs, 7H), 2.10–1.82 (m, 3H), 1.70–1.20 (m, 9H), 0.88, 0.74and 0.69 (each d, J=6.0 Hz, totally 12H).

EXAMPLE 10 (38)1-[(1R,2S)-2-(4-pyrrolidinomethylbenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamideHydrochloride

TLC: Rf 0.39 and 0.34 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 8.48 and 8.38 (each d, J=6.6 Hz, totally 1H), 7.87–7.71(m, 3H), 7.67–7.62 (m, 2H), 4.95–4.80 (m, 1H), 4.38 and 4.37 (each s,totally 2H), 4.30–4.14 (m, 1H), 3.61–3.45 (m, 2H), 3.32 (m, 2H), 3.03(m, 2H), 2.78–2.74 (m, 1H), 2.02–1.87 (m, 7H), 1.69–1.23 (m, 9H), 0.89(d, J=6.6 Hz, 3H), 0.88 (d, J=6.6 Hz, 3H), 0.84, 0.83, 0.74, and 0.69(each d, J=6.0 Hz, totally 6H).

EXAMPLE 10 (39)1-[(1R,2S)-2-(4-morpholinomethylbenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamideHydrochloride

TLC: Rf 0.36 (n-hexane:ethyl acetate=1:3);

NMR (DMSO-d₆): δ 8.38 (d, J=6.9 Hz, 1H), 7.87–7.81 (m, 3H), 7.67 (d,J=8.1 Hz, 2H), 4.93–4.86 (m, 1H), 4.38 (br-s, 2H), 4.27 (m, 1H),3.95–3.90 (m, 2H), 3.81–3.74 (m, 2H), 3.61–3.48 (m, 2H), 3.25–3.01 (m,4H), 2.78–2.71 (m, 1H), 2.07–1.86 (m, 2H), 1.66–1.23 (m, 10H), 0.89 (d,J=6.9 Hz, 3H), 0.88 (d, J=6.9 Hz, 3H), 0.75 (d, J=6.0 Hz, 3H), 0.70 (d,J=6.0 Hz, 3H).

EXAMPLE 10 (40)(4-dimethylaminomethyl)-N-[4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-(1,3,4-oxadiazolin)-5-yl)pentyl]benzamide

TLC: Rf 0.46 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.76 (d, J=8.3 Hz, 2H), 7.40 (d, J=8.3 Hz, 2H), 6.58 (d,J=8.1 Hz, 1H), 5.65–5.55 (m, 1H), 3.70 (dd, J=12.5, 7.4 Hz, 1H), 3.65(dd, J=12.5, 7.5 Hz, 1H), 3.48 (s, 2H), 2.25 (s, 6H), 2.25–2.10 (m, 1H),1.85–1.55 (m, 3H), 1.06 (d, J=6.0 Hz, 3H), 1.00 (d, J=6.0 Hz, 9H).

EXAMPLE 10 (41)(3-dimethylaminomethyl)-N-[4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-(1,3,4-oxadiazolin)-5-yl)pentyl]benzamide

TLC: Rf 0.40 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.75 (s, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.48 (d, J=7.5 Hz,1H), 7.41 (t, J=7.5 Hz, 1H), 6.71 (d, J=8.1 Hz, 1H), 5.65–5.55 (m, 1H),3.70 (dd, J=13.7, 7.1 Hz, 1H), 3.65 (dd, J=13.7, 7.2 Hz), 3.48 (s, 2H),2.26 (s, 6H), 2.25–2.10 (m, 1H), 1.90–1.60 (m, 3H), 1.06 (d, J=6.3 Hz,3H), 1.00 (d, J=6.3 Hz, 3H), 0.99 (d, J=6.9 Hz, 6H).

EXAMPLE 10 (42)1-[(1R,2S)-2-(2-dimethylaminomethyl-4-fluorobenzoylamino)cyclohexyl]-N-[4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.53 and 0.42 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 10.51 and 10.45 (each brd, J=7.2 Hz, totally 1H), 8.02and 7.99 (each t, J=5.4 Hz, totally 1H), 7.13–7.05 (m, 1H), 6.92–6.80(m, 1H), 6.83 and 6.24 (each brd, J=6.9 Hz, totally 1H), 5.26–5.10 (m,1H), 4.48 and 4.32 (each m, totally 1H), 3.80–3.30 (m, 4H), 3.10 and2.90 (each m, totally 1H), 2.50–1.21 (m, 18H), 1.10–0.70 (m, 12H).

EXAMPLE 10 (43)(2-dimethylaminomethyl)-N-[4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-(1,3,4-oxadiazolin)-5-yl)pentyl]benzamide

TLC: Rf 0.65 (chloroform methanol=9:1);

NMR (CDCl₃): δ 11.39 (d, J=5.1 Hz, 1H), 7.95–7.90 (m, 1H), 7.45–7.30 (m,1H), 7.25–7.15 (m, 1H), 5.50–5.40 (m, 1H), 4.04 (d, J=12.2 Hz, 1H), 3.69(dd, J=14.0, 7.0 Hz, 1H), 3.65 (dd, J=14.0, 7.0 Hz, 1H), 3.22 (d, J=12.2Hz, 1H), 2.30 (s, 6H), 2.20 (septet, J=7.0 Hz, 1H), 1.85–1.50 (m, 3H),1.10–0.90 (m, 12H).

EXAMPLE 10 (44)2-phenyl-N-[4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-(1,3,4-oxadiazolin)-5-yl)pentyl]benzamide

TLC: Rf 0.52 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 7.75–7.70 (m, 1H), 7.55–7.30 (m, 8H), 5.69 (d, J=7.5 Hz,1H), 5.26 (ddd, J=9.8, 7.5, 4.1 Hz, 1H), 3.65 (dd, J=13.7, 7.0 Hz, 1H),3.62 (dd, J=13.7, 7.0 Hz, 1H), 2.16 (septet, J=7.0 Hz, 1H), 1.45–1.05(m, 3H), 0.98 (d, J=7.0 Hz, 6H), 0.85 (d, J=6.3 Hz, 3H), 0.79 (d, J=6.3Hz, 3H).

EXAMPLE 10 (45)1-[1-benzoylaminocyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.68 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.89 (d, J=6.6 Hz, 1H), 7.77 (d, J=6.9 Hz, 2H), 7.56 (t,J=6.9 Hz, 1H), 7.47 (t, J=6.9 Hz, 2H), 6.09 (brs, 1H), 5.38–5.23 (m,1H), 3.64 and 3.58 (each dd, J=6.9 Hz, each 1H), 2.40–1.21 (m, 14H),1.10–0.90 (m, 12H).

EXAMPLE 10 (46)1-[(1R,2S)-2-(3-morpholinomethylbenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamideHydrochloride

TLC: Rf 0.49 and 0.38 (chloroform:methanol=19:1);

NMR (DMSO-d₆): δ 8.47 and 8.37 (each d, J=6.0 Hz, totally 1H), 8.04 and7.96 (each s, totally 1H), 7.83–7.65 (m, 3H), 7.52 (t-like, J=7.5 Hz,1H), 4.94–4.84 (m, 1H), 4.37 (br-s, 2H), 4.31 (m, 1H), 3.94–3.90 (m,2H), 3.80–3.72 (m, 2H), 3.61–3.48 (m, 2H), 3.38–3.04 (m, 4H), 2.73–2.71(m, 1H), 2.06–1.90 (m, 3H), 1.71–1.23 (m, 9H), 0.90 (d, J=6.6 Hz, 6H),0.84, 0.82, 0.75, and 0.69 (each d, J=6.0 Hz, totally 6H).

EXAMPLE 10 (47)1-[(1R,2S)-2-(3-pyrrolidinomethylbenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamideHydrochloride

TLC: Rf 0.47 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 8.37 (d, J=6.6 Hz, 1H), 8.00 (s, 1H), 7.79 (d, J=7.5Hz, 2H), 7.73 (d, J=7.5 Hz, 1H), 7.51 (t-like, J=7.5 Hz, 1H), 4.95–4.86(m, 1H), 4.39 and 4.37 (each s, totally 2H), 4.29 (m, 1H), 3.61–3.47 (m,2H), 3.41–3.22 (m, 2H), 3.05 (m, 2H), 2.74–2.72 (m, 1H), 2.01–1.84 (m,7H), 1.68–1.23 (m, 9H), 0.89 (d, J=6.6 Hz, 6H), 0.74 (d, J=6.0 Hz, 3H),0.68 (d, J=6.0 Hz, 3H).

EXAMPLE 10 (48)1-[(1R,2S)-2-(2-morpholinomethylbenzoylamino)cyclohexyl]-N-[4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-butyl]carboxamideHydrochloride

TLC: Rf 0.46 and 0.43 (chloroform:methanol=19:1);

NMR (DMSO-d₆): δ 8.55–8.30 (m, 2H), 7.76–7.69 (m, 1H), 7.59–7.49 (m,3H), 4.92–4.85 (m, 1H), 4.50–4.27 (m, 3H), 3.91–3.88 (m, 2H), 3.80–3.67(m, 2H), 3.63–3.48 (m, 2H), 3.32–3.00 (m, 4H), 2.80–2.69 (m, 1H),2.18–1.80 (m, 4H), 1.74–1.23 (m, 8H), 0.90 and 0.89 (each d, J=6.6 Hz,totally 6H), 0.81 and 0.77 (each d, J=6.3 Hz, totally 6H).

EXAMPLE 10 (49)1-[(1R,2S)-2-(4-dimethylaminomethylbenzoylamino)cyclohexyl]-N-[4-methyl-1-oxo-1-(3-cyclopropylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

Free Compound

TLC: Rf 0.43 and 0.36 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.76 and 7.72 (each d, J=8.4 Hz, totally 2H), 7.37 and7.36 (each d, J=8.4 Hz, totally 2H), 7.13 and 7.10 (each d, J=7.4 Hz,totally 1H), 6.40–6.20 (m, 1H), 5.40–5.20 (m, 1H), 4.34 (br, 1H), 3.76and 3.75 (each dd, J=14.3, 7.4 and 14.5, 7.1 Hz, totally 1H)3.63 and3.60 (each dd, J=14.3, 7.4 and 14.5, 7.6 Hz, totally 1H), 3.46 and 3.45(each s, totally 2H), 2.86 (br, 1H), 2.24 and 2.23 (each s, totally 6H),2.20–1.35 (m, 11H), 1.35–1.10 (m, 1H), 1.00, 0.94, 0.89 and 0.83 (eachd, J=6.2, 6.2, 5.8 and 5.8 Hz, totally 6H), 0.70–0.30 (m, 4H)

Hydrochloride

TLC: Rf 0.43 and 0.36 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.85 and 7.81 (each d, J=8.6 Hz, totally 2H), 7.73 and7.65 (each d, J=8.6 Hz, totally 2H), 7.47 and 7.16 (each d, J=8.0 Hz,totally 1H), 7.09 and 6.34 (each d, J=7.2 Hz, totally 1H), 5.45–5.20 (m,1H), 4.45–4.10 (m, 3H), 3.78 and 3.76 (each dd, J=14.4, 7.1 and 14.3,6.9 Hz, totally 1H), 3.64 and 3.61 (each dd, J=14.4, 7.7 and 14.3, 7.3Hz, totally 1H), 3.05–2.60 (m, 7H), 2.20–1.35 (m, 11H), 1.35–1.10 (m,1H), 1.05–0.80 (m, 6H), 0.70–0.30 (m, 4H).

EXAMPLE 10 (50)1-[(1R,2S)-2-(4-fluorobenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-cyclopropylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.41 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.78 (dd, J=8.8, 5.4 Hz, 2H), 7.18 (d, J=8.6 Hz, 1H),7.10 (t, J=8.8 Hz, 2H), 6.15 (d, J=8.0 Hz, 1H), 5.45–5.30 (m, 1H),4.40–4.20 (m, 1H), 3.77 (dd, J=14.5, 7.2 Hz, 1H), 3.64 (dd, J=14.5, 7.6Hz, 1H), 2.83 (q, J=5.1 Hz, 1H), 2.20–1.35 (m, 11H), 1.35–1.10 (m, 1H),0.91 (d, J=6.2 Hz, 3H), 0.86 (d, J=6.2 Hz, 3H), 0.70–0.35 (m, 4H).

EXAMPLE 10 (51)1-[(1R,2S)-2-(4-chlorobenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-cyclopropylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.46 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.72 (d, J=8.6 Hz, 2H), 7.40 (d, J=8.6 Hz, 2H), 7.23 (d,J=8.0 Hz, 1H), 6.14 (d, J=8.0 Hz, 1H), 5.45–5.30 (m, 1H), 4.40–4.20 (m,1H), 3.77 (dd, J=14.4, 7.0 Hz, 1H), 3.64 (dd, J=14.4, 7.7 Hz, 1H), 2.83(q, J=5.1 Hz, 1H), 2.20–1.35 (m, 11H), 1.35–1.10 (m, 1H), 0.91 (d, J=5.8Hz, 3H), 0.87 (d, J=5.8 Hz, 3H), 0.70–0.35 (m, 4H).

EXAMPLE 10 (52)1-[(1R,2S)-2-(4-methoxybenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-cyclopropylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.27 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.73 (d, J=9.0 Hz, 2H), 7.01 (d, J=8.2 Hz, 1H), 6.92 (d,J=9.0 Hz, 2H), 6.22 (d, J=7.6 Hz, 1H), 5.45–5.25 (m, 1H), 4.40–4.25 (m,1H), 3.85 (s, 3H), 3.76 (dd, J=14.5, 7.1 Hz, 1H), 3.63 (dd, J=14.5, 7.5Hz, 1H), 2.83 (q, J=5.1 Hz, 1H), 2.20–1.35 (m, 11H), 1.35–1.10 (m, 1H),0.89 (d, J=5.8 Hz, 3H), 0.84 (d, J=6.0 Hz, 3H), 0.70–0.35 (m, 4H).

EXAMPLE 10 (53)1-[(1R,2S)-2-(4-cyanobenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-cyclopropylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.37 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.88 (d, J=8.4 Hz, 2H), 7.73 (d, J=8.4 Hz, 2H), 7.53 (d,J=8.4 Hz, 1H), 6.14 (d, J=8.0 Hz, 1H), 5.45–5.30 (m, 1H), 4.40–4.20 (m,1H), 3.78 (dd, J=14.5, 7.1 Hz, 1H), 3.65 (dd, J=14.5, 7.6 Hz, 1H), 2.83(q, J=5.1 Hz, 1H), 2.20–1.35 (m, 11H), 1.35–1.10 (m, 1H), 0.93 (d, J=6.2Hz, 3H), 0.89 (d, J=6.2 Hz, 3H), 0.70–0.35 (m, 4H).

EXAMPLE 10 (54)1-[(1R,2S)-2-(N-benzoyl-N-methylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-cyclopropylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.45 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.50–7.20 (m, 5H), 6.51–6.13 (br, 1H), 5.35-5.22 (m, 1H),4.67–4.20 (br, 1H), 3.76 and 3.61 (each dd, J=14.7 and 7.2 Hz, each 1H),3.33–3.02 (br, 1H), 2.88 (s, 3H), 2.62–2.35 (m, 1H), 2.04–1.07 (m, 11H),1.07–0.79 (m, 6H), 0.70–0.56 and 0.50–0.32 (each m, each 2H).

EXAMPLE 10 (55)1-[(1R,2S)-2-(N-(4-dimethylaminobenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-cyclopropylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

Free Compound

TLC: Rf 0.26 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.66 (d, J=9.0 Hz, 2H), 6.82 (d, J=8.0 Hz, 1H), 6.66 (d,J=9.0 Hz, 2H), 6.33 (d, J=7.6 Hz, 1H), 5.40–5.25 (m, 1H), 4.45–4.30 (m,1H), 3.75 (dd, J=14.4, 7.3 Hz, 1H), 3.62 (dd, J=14.4, 7.4 Hz, 1H), 3.02(s, 6H), 2.82 (q, J=5.0 Hz, 1H), 2.15–1.35 (m, 11H), 1.30–1.10 (m, 1H),0.88 (d, J=5.8 Hz, 3H), 0.83 (d, J=6.4 Hz, 3H), 0.70–0.35 (m, 4H).

Hydrochloride

TLC: Rf 0.26 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.87 (d, J=8.4 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H), 7.42 (d,J=7.8 Hz, 1H), 6.25 (d, J=7.6 Hz, 1H), 5.45–5.20 (m, 1H), 4.40–4.20 (m,1H), 3.75 (dd, J=14.4, 7.2 Hz, 1H), 3.64 (dd, J=14.4, 7.7 Hz, 1H), 3.15(s, 6H), 2.83 (q, J=4.8 Hz, 1H), 2.15–1.35 (m, 11H), 1.35–1.10 (m, 1H),0.93 (d, J=6.2 Hz, 3H), 0.90 (d, J=6.2 Hz, 3H), 0.70–0.35 (m, 4H).

EXAMPLE 10 (56)1-[(1R,2S)-2-(2-fluorobenzoylamino)cyclohexyl]-N-[(2S)-1-oxo-1-(3-cyclopropylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-hexyl]carboxamide

TLC: Rf 0.31 (n-hexane:ethyl acetate=3:2);

NMR (CDCl₃): δ 8.05 (dt, J=2.2, 7.9 Hz, 1H), 7.60–7.40 (m, 2H), 7.25(dt, J=1.1, 7.5 Hz, 1H), 7.11 (ddd, J=12.0, 8.2, 1.1 Hz, 1H), 6.36 (d,J=7.6 Hz, 1H), 5.30 (dt, J=4.2, 7.6 Hz, 1H), 4.55–4.35 (m, 1H), 3.73(dd, J=14.5, 7.2 Hz, 1H), 3.64 (dd, J=14.5, 7.6 Hz, 1H), 2.83 (q, J=5.0Hz, 1H), 2.20–1.05 (m, 15H), 0.85–0.70 (m, 3H), 0.70–0.35 (m, 4H).

EXAMPLE 10 (57)1-[(1R,2S)-2-(4-dimethylaminobenzoylamino)cyclohexyl]-N-[(2S)-1-oxo-1-(3-cyclopropylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-hexyl]carboxamide

Free Compound

TLC: Rf 0.22 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.67 (d, J=9.0 Hz, 2H), 6.88 (d, J=8.2 Hz, 1H), 6.67 (d,J=9.0 Hz, 2H), 6.44 (d, J=7.2 Hz, 1H), 5.24 (ddd, J=8.4, 7.2 and 4.8 Hz,1H), 4.45–4.30 (m, 1H), 3.74 (dd, J=14.2, 7.2 Hz, 1H), 3.65 (dd, J=14.2,7.2 Hz, 1H), 3.01 (s, 6H), 2.82 (q, J=5.0 Hz, 1H), 2.15–1.15 (m, 15H),0.85–0.70 (m, 3H), 0.70–0.35 (m, 4H).

Hydrochloride

TLC: Rf 0.22 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.88 (d, J=8.4 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.46 (d,J=8.2 Hz, 1H), 6.40 (d, J=8.0 Hz, 1H), 5.28 (dt, J=4.7, 8.0 Hz, 1H),4.40–4.20 (m, 1H), 3.75 (dd, J=14.9, 7.4 Hz, 1H), 3.67 (dd, J=14.9, 7.8Hz, 1H), 3.16 (s, 6H), 2.84 (q, J=5.1 Hz, 1H), 2.15–1.15 (m, 15H),0.90–0.70 (m, 3H), 0.70–0.35 (m, 4H).

EXAMPLE 10 (58)1-[(1R,2S)-2-(4-dimethylaminomethylbenzoylamino)cyclohexyl]-N-[1-oxo-1-(3-cyclopropylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-hexyl]carboxamide

Free Compound

TLC: Rf 0.47 and 0.38 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.76 and 7.73 (each d, J=8.0 and 8.2 Hz, totally 2H),7.37 and 7.36 (each d, J=8.0 and 8.2 Hz, totally 2H), 7.17 (d, J=8.0 Hz,1H), 6.45–6.30 (m, 1H), 5.35–5.15 (m, 1H), 4.45–4.25 (m, 1H), 3.75 and3.73 (each dd, J=14.4, 7.1 Hz, totally 1H), 3.66 and 3.63 (each dd,J=14.4, 7.4 Hz, totally 1H), 3.46 (s, 2H), 2.90–2.80 (m, 1H), 2.24 (s,6H), 2.20–1.10 (m, 15H), 0.90–0.70 (m, 3H), 0.70–0.35 (m, 4H).

Hydrochloride

TLC: Rf 0.47 and 0.38 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.87 and 7.83 (each d, J=8.4 and 8.6 Hz, totally 2H),7.72 and 7.66 (each d, J=8.4 and 8.6 Hz, totally 2H), 7.51 and 7.22(each d, J=8.0 Hz, totally 1H), 6.91 and 6.39 (each d, J=6.6 and 7.8 Hz,totally 1H), 5.40–5.10 (m, 1H), 4.40–4.10 (m, 3H), 3.85–3.55 (m, 2H),3.00–2.60 (m, 7H), 2.30–1.10 (m, 15H), 0.95–0.70 (m, 3H), 0.70–0.35 (m,4H).

EXAMPLE 10 (59)1-[(1R,2S)-2-(4-pyrrolidinomethylbenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-cyclopropylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamideHydrochloride

TLC: Rf 0.30 and 0.35 (chloroform:methanol=9:1);

NMR (DMSO-d₆) δ 8.50 and 8.39 (each d, J=6.3 Hz, totally 1H), 7.88–7.62(m, 5H), 4.94–4.81 (m, 1H), 4.38 and 4.37 (each s, totally 2H),4.32–4.12 (m, 1H), 3.70–3.50 (m, 2H), 3.38–3.25 (m, 2H), 3.08–2.96 (m,2H), 2.80–2.72 (m, 1H), 2.00–1.88 (m, 7H), 1.68–1.22 (m, 8H), 1.17–1.06(m, 1H), 0.86, 0.84, 0.75, and 0.71 (each d, J=6.3 Hz, totally 6H),0.53–0.49 (m, 2H), 0.36–0.33 (m, 2H).

EXAMPLE 10 (60)1-[(1R,2S)-2-(4-morpholinomethylbenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-cyclopropylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamideHydrochloride

TLC: Rf 0.53 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 8.40 (d, J=6.9 Hz, 1H), 7.87–7.81 (m, 3H), 7.66 (d,J=7.8 Hz, 2H), 4.93–4.86 (m, 1H), 4.37 (m, 2H), 4.27 (m, 1H), 3.95–3.90(m, 2H), 3.81–3.73 (m, 2H), 3.67–3.54 (m, 2H), 3.41–3.05 (m, 4H),2.79–2.72 (m, 1H), 2.06–1.87 (m, 1H), 1.56–1.23 (m, 10H), 1.17–1.06 (m,1H), 0.76 (d, J=6.3 Hz, 3H), 0.72 (d, J=6.3 Hz, 3H), 0.52–0.50 (m, 2H),0.36–0.33 (m, 2H).

EXAMPLE 10 (61)1-[(1R,2S)-2-(2-dimethylaminomethyl-4-fluorobenzoylamino)cyclohexyl]-N-[4-methyl-1-oxo-1-(3-cyclopropylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.53 and 0.44 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 10.50 and 10.44 (each brd, J=7.2 Hz, totally 1H), 8.03and 7.99 (each t, J=5.4 Hz, totally 1H), 7.10–7.03 (m, 1H), 6.93–6.88(m, 1H), 6.85 and 6.23 (each brd, J=7.5 Hz, totally 1H), 5.30–5.10 (m,1H), 4.50 and 4.31 (each m, totally 1H), 3.80–3.30 (m, 4H), 3.05 and2.92 (each m, totally 1H), 2.24 and 2.21 (each s, totally 6H), 2.30–1.10(m, 12H), 0.99 and 0.78 (each m, totally 6H), 0.63 and 0.43 (each m,each 2H).

EXAMPLE 10 (62)1-[(1R,2S)-2-(3-pyrrolidinomethylbenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-cyclopropylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamideHydrochloride

TLC: Rf0.35 (chloroform methanol=9:1);

NMR (DMSO-d₆) δ 8.49 and 8.38 (each d, J=6.6 Hz, totally 1H), 8.01 and7.93 (each s, totally 1H), 7.80 (d, J=7.5 Hz, 2H), 7.74 (d, J=7.8 Hz,1H), 7.51 (t-like, J=7.5 Hz, 1H), 4.93–4.87 (m, 1H), 4.39 and 4.37 (eachs, totally 2H), 4.38 (m, 1H), 3.87–3.53 (m, 2H), 3.38–3.32 (m, 2H), 3.05(m, 2H), 2.75–2.72 (m, 1H), 2.01–1.87 (m, 7H), 1.58–1.24 (m, 8H),1.17–1.05 (m, 1H), 0.86, 0.84, 0.76, and 0.70 (each d, J=6.0 Hz, totally6H), 0.54–0.48 (m, 2H), 0.36–0.33 (m, 2H).

EXAMPLE 10 (63)1-[(1R,2S)-2-(4-dimethylaminomethyl-2-fluorobenzoylamino)cyclohexyl]-N-[4-methyl-1-oxo-1-(3-cyclopropylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.57 and 0.50 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 8.02–7.92 (m, 1H), 7.48–7.35 (m, 1H), 7.21–7.05 (m, 2H),6.39 and 6.22 (each brd, J=6.9 Hz, totally 1H), 5.42–5.25 (m, 1H),4.52–4.38 (m, 1H), 3.80–3.54 (m, 1H), 3.43 (m, 2H), 2.82–2.75 (m, 1H),2.24 (s, 6H), 2.15–1.40 (m, 11H), 1.30–1.15 (m, 1H), 0.99, 0.96, 0.87,and 0.80 (each d, J=6.3 Hz, totally 6H), 0.70 and 0.42 (each m, each2H).

EXAMPLE 10 (64)1-[(1R,2S)-2-(4-dimethylaminobenzoylamino)cyclohexyl]-N-[4-methyl-1-oxo-1-(3-cyclopropylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.38 (toluene:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.72 and 7.66 (each d, J=8.7 Hz, totally 2H), 6.87 and6.81 (each d, J=8.4 Hz, totally 1H), 6.66 and 6.65 (each d, J=8.7 Hz,totally 2H), 6.33–6.29 (m, 1H), 5.35–5.20 (m, 1H), 4.38–4.33 (m, 1H),3.79–3.70 (m, 1H), 3.65–3.55 (m, 1H), 3.01 (m, 6H), 2.88–2.80 (m, 1H),2.15–1.45 (m, 11H), 1.29–1.16 (m, 1H), 0.99–0.82 (m, 6H), 0.64–0.61 (m,2H), 0.42 (m, 2H).

EXAMPLE 10 (65) 1-[(1R,2S)-2-(3-dimethylaminomethylbenzoylamino)cyclohexyl]-N-[4-methyl-1-oxo-1-(3-cyclopropylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.48 and 0.46 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.75–7.60 (m, 2H), 7.50–7.30 (m, 2H), 7.09 (d, J=8.4 Hz,1H), 6.31 and 6.26 (each d, J=7.8 and 8.0 Hz, totally 1H), 5.40–5.20 (m,1H), 4.45–4.25 (m, 1H), 3.76 and 3.75 (each dd, J=14.5, 7.2 Hz, totally1H), 3.63 and 3.61 (each dd, J=14.5, 7.4 Hz, totally 1H), 3.47 (s, 2H),2.90–2.80 (m, 1H), 2.25 and 2.24 (each s, totally 6H), 2.20–1.35 (m,11H), 1.35–1.10 (m, 1H), 1.00, 0.94, 0.88 and 0.83 (each d, J=6.2 Hz,totally 6H), 0.70–0.35 (m, 4H).

EXAMPLE 10 (66)1-[(1R,2S)-2-(2-dimethylaminomethylbenzoylamino)cyclohexyl]-N-[4-methyl-1-oxo-1-(3-cyclopropylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.42 and 0.36 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 10.65–10.45 (m, 1H), 8.05–7.90 (m, 1H), 7.45–7.30 (m,2H), 7.25–7.10 (m, 1H), 7.00 and 6.34 (each d, J=7.0 and 7.2 Hz, totally1H), 5.30–5.10 (m, 1H), 4.52 and 4.34 (each br, totally 1H), 3.80–3.30(m, 4H), 3.10–2.85 (m, 1H), 2.23 and 2.21 (each s, totally 6H),2.20–1.35 (m, 11H), 1.30–1.10 (m, 1H), 0.96, 0.95, 0.71 and 0.68 (eachd, J=6.2, 6.2, 6.0 and 6.0 Hz, totally 6H), 0.65–0.35 (m, 4H).

EXAMPLE 10 (67)(2S)-N-[2-oxo-2-(3-cyclopropylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)ethyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.73 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.46–7.24 (m, 5H), 6.98–6.79 (br, 1H), 5.34–5.18 (m, 1H),5.12 (s, 2H), 4.60 (brs, 2H), 4.37–4.22 (m, 1H), 3.69 (d, J=7.5 Hz, 2H),2.00–1.46 (m, 3H), 1.32–1.18 (m, 1H), 1.10–0.90 (m, 6H), 0.70–0.57 and0.47–0.38 (each m, totally 4H).

EXAMPLE 10 (68)(2S)-N-[(2S)-4-methoxy-1-oxo-1-(3-cyclopropylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-butyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.43 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.40–7.25 (m, 5H), 7.13 (d, J=6.0 Hz, 1H), 5.28 (q, J=6.0Hz, 1H), 5.20–5.05 (m, 3H), 4.30–4.15 (m, 1H), 3.71 (dd, J=14.2, 7.5 Hz,1H), 3.67 (dd, J=14.2, 7.5 Hz, 1H), 3.50–3.30 (m, 2H), 3.19 (s, 3H),2.25–2.10 (m, 2H), 1.80–1.40 (m, 3H), 1.30–1.15 (m, 1H), 0.95 (d, J=6.3Hz, 6H), 0.65–0.60 (m, 2H), 0.45–0.40 (m, 2H).

EXAMPLE 10 (69)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[(2S)-4-methoxy-1-oxo-1-(3-cyclopropylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-butyl]carboxamide

TLC: Rf 0.42 (n-hexane:ethyl acetate=1:2);

NMR (CDCl₃) δ 7.80–7.75 (m, 2H), 7.50–7.35 (m, 4H), 7.10 (d, J=6.0 Hz,1H), 5.28 (q, J=6.0 Hz, 1H), 4.40–4.30 (m, 1H), 3.70 (dd, J=14.5, 7.2Hz, 1H), 3.66 (dd, J=14.5, 7.2 Hz, 1H), 3.40 (t, J=6.0 Hz, 2H), 3.21 (s,3H), 2.81 (q, J=4.8 Hz, 1H), 2.17 (q, J=6.0 Hz, 2H), 2.05–1.45 (m, 8H),1.30–1.15 (m, 1H), 0.65–0.60 (m, 2H), 0.45–0.40 (m, 2H).

EXAMPLE 10 (70)1-[(1R,2S)-2-(3-morpholinomethylbenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-cyclopropylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamideHydrochloride

TLC: Rf 0.49 (chloroform:methanol=19:1);

NMR (DMSO-d₆) δ 8.48 and 8.38 (each d, J=6.6 Hz, totally 1H), 8.03 and7.96 (each s, totally 1H), 7.81 (d, J=6.3 Hz, 2H), 7.72 (d, J=7.5 Hz,1H), 7.53 (t-like, J=7.5 Hz, 1H), 4.92–4.86 (m, 1H), 4.39 (br-s, 2H),4.30 (m, 1H), 3.95–3.91 (m, 2H), 3.78–3.69 (m, 2H), 3.67–3.53 (m, 2H),3.41–3.08 (m, 4H), 2.74–2.72 (m, 1H), 2.02–1.90 (m, 2H), 1.79–1.21 (m,9H), 1.18–1.04 (m, 1H), 0.86, 0.84, 0.76, and 0.71 (each d, J=6.0 Hz,totally 6H), 0.54–0.48 (m, 2H), 0.35–0.33 (m, 2H).

EXAMPLE 10 (71)1-[(1R,2S)-2-(2-morpholinomethylbenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-cyclopropylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamideHydrochloride

TLC: Rf 0.56 (chloroform:methanol=19:1);

NMR (DMSO-d₆): δ 8.56–8.21 (m, 2H), 7.75–7.70 (m, 1H), 7.59–7.53 (m,3H), 4.92–4.85 (m, 1H), 4.50–4.33 (m, 3H), 3.91–3.88 (m, 2H), 3.79–3.55(m, 4H), 3.38–3.08 (m, 4H), 2.80–2.71 (m, 1H), 1.98–1.77 (m, 2H),1.67–1.22 (m, 9H), 1.18–1.06 (m, 1H), 0.89, 0.83, and 0.79 (each d,J=6.0 Hz, totally 6H), 0.56–0.49 (m, 2H), 0.37–0.34 (m, 2H).

EXAMPLE 10 (72)(2S)-N-[(2S)-1-oxo-1-(3-cyclopropylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.44 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 7.34 (s, 5H), 6.58 (brd, J=7.4 Hz, 1H), 5.29 (m, 1H),5.11 (m, 3H), 4.22 (m, 1H), 3.74 and 3.64 (each dd, J=14.8, 7.4 Hz, each1H), 2.03–1.80 (m, 1H), 1.80–1.10 (m, 9H), 1.02–0.80 (m, 9H), 0.60 and0.43 (each m, each 2H).

EXAMPLE 10 (73)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[(2S)-1-oxo-1-(3-cyclopropylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-hexyl]carboxamide

TLC: Rf 0.65 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.80 (m, 2H), 7.58–7.31 (m, 3H), 7.20 (brd, J=8.2 Hz,1H), 6.27 (brd, J=7.6 Hz, 1H), 5.29 (ddd, J=8.4, 7.6, 4.4 Hz, 1H), 4.38(m, 1H), 3.75 and 3.64 (each dd, J=14.4, 7.4 Hz, each 1H), 2.83 (q,J=5.2 Hz, 1H), 2.23–1.13 (m, 15H), 0.83 (m, 3H), 0.63 and 0.82 (each m,each 2H).

EXAMPLE 10 (74)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-cyclohexyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.31 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.83–7.74 (m, 2H), 7.53–7.37 (m, 3H), 7.14 (d, J=8.1 Hz,1H), 6.17 (d, J=7.8 Hz, 1H), 5.42–5.24 (m, 1H), 4.40–4.28 (m, 1H), 4.03(tt, J=11.4, 3.9 Hz, 1H), 2.88–2.80 (m, 1H), 2.17–1.12 (m, 21H), 0.90and 0.83 (each d, J=6.3 Hz, totally 6H).

EXAMPLE 10 (75)(2S)-N-[(2S)-4-methyl-1-oxo-1-(3-ethoxymethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.37 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 7.35 (s, 5H), 6.50 (d, J=7.0 Hz, 1H), 5.40–5.25 (m, 1H),5.21 (s, 2H), 5.15–5.05 (m, 1H), 5.12 (s, 2H), 4.30–4.10 (m, 1H), 3.69(q, J=7.0 Hz, 2H), 1.80–1.40 (m, 6H), 1.24 (t, J=7.0 Hz, 3H), 1.10–0.80(m, 12H).

EXAMPLE 10 (76)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-ethoxymethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.40 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.76 (dd, J=8.6, 2.0 Hz, 2H), 7.60–7.35 (m, 3H), 7.11 (d,J=8.0 Hz, 1H), 6.19 (d, J=7.2 Hz, 1H), 5.40–5.25 (m, 1H), 5.20 (s, 2H),4.45–4.25 (m, 1H), 3.69 (q, J=7.0 Hz, 2H), 2.85 (q, J=5.0 Hz, 1H),2.20–1.30 (m, 11H), 1.24 (t, J=7.0 Hz, 3H), 0.88 (d, J=6.0 Hz, 3H), 0.84(d, J=6.0 Hz, 3H).

EXAMPLE 10 (77)(2S)-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methoxyethyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.45 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.35 (s, 5H), 6.50 (d, J=7.4 Hz, 1H), 5.40–5.25 (m, 1H),5.20–5.05 (m, 3H), 4.30–4.10 (m, 1H), 4.04 (dt, J=14.3, 5.5 Hz, 1H),4.00 (dt, J=14.3, 5.1 Hz, 1H), 3.72 (t, J=5.3 Hz, 2H), 3.36 (s, 3H),1.80–1.40 (m, 6H), 1.05–0.80 (m, 12H).

EXAMPLE 10 (78)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-methoxyethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.16 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.77 (dd, J=7.9, 1.6 Hz, 2H), 7.55–7.35 (m, 3H), 7.14 (d,J=8.4 Hz, 1H), 6.19 (d, J=7.8 Hz, 1H), 5.40–5.25 (m, 1H), 4.40–4.25 (m,1H), 4.04 (dt, J=14.5, 5.6 Hz, 1H), 3.99 (dt, J=14.5, 5.0 Hz, 1H), 3.72(t, J=5.3 Hz, 2H), 3.36 (s, 3H), 2.84 (q, J=5.2 Hz, 1H), 2.20–1.35 (m,11H), 0.88 (d, J=6.0 Hz, 3H), 0.83 (d, J=6.2 Hz, 3H).

EXAMPLE 10 (79)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-butyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf0.45 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.77 (dd, J=7.9, 1.6 Hz, 2H), 7.55–7.35 (m, 3H), 7.13 (d,J=8.0 Hz, 1H), 6.19 (d, J=8.2 Hz, 1H), 5.40–5.25 (m, 1H), 4.40–4.25 (m,1H), 3.84 (t, J=7.0 Hz, 2H), 2.84 (q, J=5.0 Hz, 1H), 2.20–1.20 (m, 15H),0.97 (t, J=7.3 Hz, 3H), 0.89 (d, J=6.0 Hz, 3H), 0.83 (d, J=6.0 Hz, 3H).

EXAMPLE 10 (80)1-[(1R,2S)-2-(4-fluorobenzoylamino)cyclohexyl]-N-[(2S)-1-oxo-1-(3-cyclopropylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-hexyl]carboxamide

TLC: Rf 0.36 (n-hexane:ethyl acetate=3:2);

NMR (CDCl₃): δ 7.79 (dd, J=8.7, 5.4 Hz, 2H), 7.35–7.20 (m, 1H), 7.10 (t,J=8.7 Hz, 2H), 6.27 (d, J=7.6 Hz, 1H), 5.30 (dt, J=4.2, 7.6 Hz, 1H),4.40–4.20 (m, 1H), 3.75 (dd, J=14.6, 7.2 Hz, 1H), 3.67 (dd, J=14.6, 7.6Hz, 1H), 2.83 (q, J=5.0 Hz, 1H), 2.20–1.10 (m, 15H), 0.90–0.70 (m, 3H),0.70–0.35 (m, 4H).

EXAMPLE 10 (81)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[(2S)-4-methyl1-oxo-1-(3-bis(methoxycarbonyl)methyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.58 (ethyl acetate);

NMR (CDCl₃): δ 7.80–7.73 (m, 2H), 7.53–7.37 (m, 3H), 7.14 (brd, J=7.8Hz, 1H), 6.18 (d, J=7.2 Hz, 1H), 5.52 (s, 1H), 5.34–5.24 (m, 1H),4.42–4.29 (m, 1H), 3.89 and 3.88 (each s, totally 6H), 2.89–2.80 (m,1H), 2.15–1.40 (m, 11H), 0.86 and 0.84 (each d, J=6.0 Hz, totally 6H).

EXAMPLE 10 (82)(2S)-N-[(2S)-4-methyl-1-oxo-1-(3-bis(methoxycarbonyl)methyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.54 (n-hexane:ethyl acetate=1:2);

NMR (CDCl₃): δ 7.48–7.25 (m, 5H), 6.60–6.40 (br, 1H), 5.52 (s, 1H),5.32–5.22 (m, 1H), 5.20–5.05 (m, 3H), 4.28–4.13 (m, 1H), 3.89 and 3.88(each s, totally 6H), 1.80–1.42 (m, 6H), 1.10–0.85 (m, 12H).

EXAMPLE 10 (83)(2S)-N-[(2S)-3-ethoxy-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-propyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.55 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.35 (s, 5H), 7.00 and 6.82 (each brd, J=7.8 Hz, totally1H), 5.45–5.38 (m, 1H), 5.22–5.10 (m, 3H), 4.35–4.20 (m, 1H), 4.03 and3.72 (each m, each 1H), 3.65 (d, J=7.2 Hz, 2H), 3.50–3.38 (m, 2H),2.30–2.10 (m, 1H), 1.80–1.50 (m, 3H), 1.15 (t, J=6.8 Hz, 3H), 1.05–0.90(m, 12H).

EXAMPLE 10 (84)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[(2S)-3-ethoxy-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-propyl]carboxamide

TLC: Rf 0.56 (n-hexane:ethyl acetate=2:3);

NMR (CDCl₃): δ 7.82 and 7.78 (each d, J=6.6 Hz, totally 2H), 7.50–7.30(m, 4H), 6.59 and 6.54 (each brd, J=6.6 Hz, totally 1H), 5.42–5.30 (m,1H), 4.42–4.30 (m, 1H), 3.98 and 3.70 (each m, each 1H), 3.65 (d, J=7.2Hz, 2H), 3.45–3.35 (m, 2H), 2.92–2.84 (m, 1H), 2.30–1.40 (m, 9H), 1.15(t, J=7.2 Hz, 3H), 1.05–0.90 (m, 6H).

EXAMPLE 10 (85)1-[(2S)-2-phenylaminocarbonylpiperidino]-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.51 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 8.51 (brs, 1H), 7.57–7.48 (m, 2H), 7.36–7.24 (m, 2H),7.13–7.05 (m, 1H), 5.28 (ddd, J=9.9, 8.1 and 4.2 Hz, 1H), 5.08 (d, J=8.1Hz, 1H), 4.88–4.77 (m, 1H), 3.70–3.56 (m, 3H), 3.12 (td, J=13.2 and 2.7Hz, 1H), 2.38–2.09 (m, 2H), 1.94–1.42 (m, 8H), 1.10–0.91 (m, 12H).

EXAMPLE 10 (86)1-[(1R,2S)-2-t-butoxycarbonylaminocyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-((1R,2S)-2-t-butoxycarbonylaminocyclohexylcarbonyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.50 (n-hexane:ethyl acetate=3:2);

NMR (CDCl₃): δ 6.21 (d, J=6.9 Hz, 1H), 5.40–5.25 (m, 1H), 5.15 (d, J=7.5Hz, 1H), 4.90 (d, J=9.3 Hz, 1H), 4.40–4.25 (m, 1H), 3.90–3.80 (m, 1H),3.50–3.40 (m, 1H), 2.69 (q, J=5.1 Hz, 1H), 1.95–1.30 (m, 19H), 1.43 (s,9H), 1.41 (s, 9H), 1.02 (d, J=6.0 Hz, 6H), 0.98 (d, J=6.3 Hz, 6H).

EXAMPLE 10 (87)(2S)-N-[4-methyl-1-oxo-1-(3-(2-dimethylaminoethyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf0.47 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.35 (s, 5H), 6.63 and 6.48 (each br, totally 1H), 5.38(m, 1H), 5.22–5.00 (m, 3H), 4.30–4.18 (m, 1H), 4.02–3.80 (m, 2H),2.80–2.60 (m, 2H), 2.27 (s, 6H), 2.05–1.40 (m, 6H), 1.02–0.80 (m, 12H).

EXAMPLE 10 (88)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[4-methyl-1-oxo-1-(3-(2-dimethylamino)ethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.40 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.83–7.71 (m, 2H), 7.50–7.38 (m, 3H), 7.20–7.10 (m, 1H),6.25 and 6.19 (each d, J=6.6 Hz, totally 1H), 5.40–5.24 (m, 1H),4.42–4.30 (m, 1H), 4.02–3.80 (m, 2H), 2.82 (m, 1H), 2.80–2.60 (m, 2H),2.28 (s, 6H), 2.25–1.40 (m, 11H), 0.98, 0.94, 0.88, and 0.82 (each d,J=6.3 Hz, totally 6H).

EXAMPLE 10 (89)(2S)-N-[(2S)-4-methoxy-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-butyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.54 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.40–7.25 (m, 5H), 7.11 (d, J=6.3 Hz, 1H), 5.26 (q, J=6.3Hz, 1H), 5.20–5.05 (m, 3H), 4.30–4.15 (m, 1H), 3.63 (d, J=7.2 Hz, 2H),3.50–3.30 (m, 2H), 3.18 (s, 3H), 2.25–2.10 (m, 3H), 1.80–1.40 (m, 3H),1.00–0.85 (m, 12H).

EXAMPLE 10 (90)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[(2S)-4-methoxy-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-butyl]carboxamide

TLC: Rf 0.22 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃) δ 7.80–7.75 (m, 2H), 7.50–7.35 (m, 4H), 7.09 (d, J=5.7 Hz,1H), 5.26 (q, J=5.7 Hz, 1H), 4.40–4.25 (m, 1H), 3.63 (d, J=6.9 Hz, 2H),3.45–3.30 (m, 2H), 3.19 (s, 3H), 2.81 (q, J=5.1 Hz, 1H), 2.25–1.40 (m,11H), 0.98 (d, J=6.9 Hz, 6H).

EXAMPLE 10 (91)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[2-oxo-2-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)ethyl]carboxamide

TLC: Rf 0.51 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.82–7.75 (m, 2H), 7.52–7.37 (m, 3H), 7.27 (brd, J=7.8Hz, 1H), 6.56–6.46 (br, 1H), 4.56 (d, J=5.1 Hz), 4.43–4.32 (m, 1H), 3.63(d, J=7.2 Hz, 2H), 2.92–2.84 (m, 1H), 2.23–1.45 (m, 9H), 0.97 (d, J=6.6Hz, 6H).

EXAMPLE 10 (92)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[2-oxo-2-(3-cyclopropylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)ethyl]carboxamide

TLC: Rf 0.47 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.83–7.75 (m, 2H), 7.55–7.38 (m, 3H), 7.28 (brd, J=9.0Hz, 1H), 6.46 (brs, 1H), 4.61 (dd, J=19.5, 5.1 Hz, 1H), 4.58 (dd,J=19.5, 5.1 Hz, 1H), 4.44–4.31 (m, 1H), 3.68 (d, J=7.5 Hz, 2H),2.92–2.84 (m, 1H), 2.13–1.13 (m, 9H), 0.68–0.59 and 0.47–0.38 (each m,totally 4H).

EXAMPLE 10 (93)(2S)-N-[2-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-oxoethyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.68 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.44–7.24 (m, 5H), 6.94–6.78 (br, 1H), 5.31–5.19 (m, 1H),5.12 (s, 2H), 4.59 (brd, J=4.2 Hz, 2H), 4.35–4.23 (m, 1H), 3.64 (d,J=7.2 Hz, 2H), 2.26–2.10 (m, 1H), 1.90–1.47 (m, 3H), 1.03–0.82 (m, 12H).

EXAMPLE 10 (94)(2S)-N-[3-cyclopropyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-propyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.45 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 7.40–7.30 (m, 5H), 6.94 and 6.74 (br and d, J=6.6 Hz,totally 1H), 5.38 (q, J=6.6 Hz, 1H), 5.20–5.00 (m, 3H), 4.30–4.15 (m,1H), 3.65 and 3.64 (each d, J=7.0 Hz, totally 2H), 2.18 (septet, J=7.0Hz, 1H), 1.90–1.40 (m, 5H), 1.00–0.85 (m, 12H), 0.75–0.55 (m, 1H),0.55–0.40 (m, 2H), 0.10–0.00 (m, 2H).

EXAMPLE 10 (95)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[3-cyclopropyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-propyl]carboxamide

TLC: Rf 0.43 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.85–7.70 (m, 2H), 7.50–7.30 (m, 3H), 7.30–7.20 (m, 1H),6.45 (d, J=6.6 Hz, 1H), 5.35 and 5.32 (each q, J=6.6 Hz, totally 1H),4.40–4.30 (m, 1H), 3.70–3.55 (m, 2H), 2.90–2.80 (m, 1H), 2.25–2.10 (m,1H), 2.10–1.40 (m, 10H), 0.97 and 0.96 (each d, J=6.6 Hz, totally 6H),0.70–0.55 (m, 1H), 0.50–0.30 (m, 2H), 0.10–0.10 (m, 2H).

EXAMPLE 10 (96)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-t-butoxycarbonylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.39 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.76 (d, J=6.9 Hz, 2H), 7.53–7.37 (m, 3H), 7.14 (brd,J=7.8 Hz, 1H), 6.18 (d, J=7.5 Hz, 1H), 5.36–5.26 (m, 1H), 4.53 (d,J=17.4 Hz, 1H), 4.44.(d, J=17.4 Hz, 1H), 4.39–4.27 (m, 1H), 2.84 (q,J=5.1 Hz, 1H), 2.15–1.38 (m, 11H), 1.49 (s, 9H), 0.87 and 0.83 (each d,J=6.0 Hz, totally 6H).

EXAMPLE 10 (97)(2S)-N-[(2S)-4-methyl-1-oxo-1-(3-t-butoxycarbonylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.58 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.43–7.24 (m, 5H), 6.50 (brd, J=7.5 Hz, 1H), 5.34–5.24(m, 1H), 5.20–5.00 (m, 1H), 5.12 (s, 2H), 4.53 (d, J=17.4 Hz, 1H), 4.44(d, J=17.4 Hz, 1H), 4.26–4.08 (m, 1H), 1.80–1.30 (m, 6H), 1.49 (s, 9H),1.05–0.80 (m, 12H).

EXAMPLE 10 (98)1-[(1R,2S)-2-(2-pyrrolidinomethylbenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamideHydrochloride

TLC: Rf 0.64 and 0.56(dichloromethane:methanol=7:1);

NMR (DMSO-d₆): δ 8.54 and 8.46 (each d, J=6.0 Hz, totally 1H), 8.40 and8.25 (each d, J=8.4 Hz, totally 1H), 7.77–7.73 (m, 1H), 7.57–7.49 (m,3H), 4.91–4.84 (m, 1H), 4.47–4.32 (m, 3H), 3.65–3.49 (m, 2H), 3.41–3.01(m, 4H), 2.77–2.68 (m, 1H), 2.05–1.80 (m, 7H), 1.70–1.22 (m, 9H), 0.91(d, J=6.6 Hz, 3H), 0.90 (d, J=6.6 Hz, 3H), 0.87, 0.81, and 0.78 (each d,J=6.3 Hz, totally 6H).

EXAMPLE 10 (99)1-[(1R,2S)-2-(3-pyrrolidinomethylbenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-cyclopropylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamideHydrochloride

TLC: Rf 0.47 and 0.40 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 8.54 and 8.47 (each d, J=6.3 Hz, totally 1H), 8.42 and8.25 (each d, J=8.1 Hz, totally 1H), 7.74–7.72 (m, 1H), 7.56–7.52 (m,3H), 4.92–4.85 (m, 1H), 4.47–4.27 (m, 3H), 3.73–3.55 (m, 2H), 3.41–3.00(m, 4H), 2.78–2.70 (m, 1H), 2.11–1.78 (m, 6H), 1.72–1.23 (m, 9H),1.18–1.06 (m, 1H), 0.89, 0.87, 0.83, and 0.79 (each d, J=6.0 Hz, totally6H), 0.57–0.46 (m, 2H), 0.37–0.32 (m, 2H).

EXAMPLE 10 (100)1-[(1R,2S)-2-(2-aminopyridin-5-ylcarbonylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-cyclopropylmethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf0.37 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 8.50 (d, J=2.2 Hz, 1H), 7.84 (dd, J=8.8, 2.2 Hz, 1H),7.02 (d, J=7.6 Hz, 1H), 6.49 (d, J=8.8 Hz, 1H), 6.26 (d, J=7.8 Hz, 1H),5.40–5.20 (m, 1H), 4.84 (br, 2H), 4.40–4.20 (m, 1H), 3.77 (dd, J=14.5,7.1 Hz, 1H), 3.64 (dd, J=14.5, 7.5 Hz, 1H), 2.82 (q, J=5.1 Hz, 1H),2.20–1.35 (m, 11H), 1.35–1.10 (m, 1H), 0.91 (d, J=5.8 Hz, 3H), 0.87 (d,J=6.2 Hz, 3H), 0.70–0.30 (m, 4H).

EXAMPLE 10 (101)1-[(1R,2S)-2-(2-dimethylaminomethylbenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamideHydrochloride

TLC: Rf 0.32 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 9.82 (brs, 1H), 8.52–8.42 (m, 2H), 7.67 (d, J=7.5 Hz,1H), 7.62–7.47 (m, 3H), 4.93–4.84 (m, 1H), 4.45–4.20 (m, 3H), 3.60 and3.53 (each dd, J=15.1, 6.9 Hz, totally 2H), 2.85–2.62 (m, 7H), 2.08–1.10(m, 12H), 0.91 and 0.90 (each d, J=6.9 Hz, totally 6H), 0.80 and 0.75(each d, J=6.3 Hz).

EXAMPLE 10 (102)1-[(1R,2S)-2-(2-butynoylamino)cyclohexyl]-N-[4-methyl-1-oxo-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.45 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 6.70 and 6.61 (each brd, J=9.0 Hz, 1H), 6.23 and 6.13(each brd, J=7.5 Hz, 1H), 5.33 and 5.27 (each m, 1H), 4.20–4.08 (m, 1H),3.70 (dd, J=14, 7.2 Hz, 1H), 3.63 (dd, J=14, 7.2 Hz, 1H), 2.79–2.71 (m,1H), 2.18 (septet J=6.9 Hz, 1H), 2.00–1.35 (m, 11H), 1.93 (s, 3H), 1.01(d, J=6.3 Hz, 3H), 1.00 (d, J=6.9 Hz, 6H), 0.97 (d, J=6.0 Hz, 3H).

EXAMPLE 10 (103)1-[(1R,2S)-2-(4-(dimethylamino)but-2-ynoylamino)cyclohexyl]-N-[4-methyl-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.46 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 6.79 and 6.73 (each brd, J=9.0 Hz, 1H), 6.20 and 6.14(each brd, J=7.5 Hz, 1H), 5.38–5.24 (each m, 1H), 4.22–4.10 (m, 1H),3.70 (dd, J=14, 7.2 Hz, 1H), 3.63 (dd, J=14, 7.2 Hz, 1H), 3.36 (s, 2H),2.80–2.72 (m, 1H), 2.32 (s, 6H), 2.19 (septet J=6.9 Hz, 1H), 2.00–1.35(m, 11H), 1.01 (d, J=6.0 Hz, 3H), 1.00 (d, J=6.6 Hz, 6H), 0.98 (d, J=6.0Hz, 3H).

EXAMPLE 10 (104)1-[(1R,2S)-2-(4-morpholinobut-2-ynoylamino)cyclohexyl]-N-[4-methyl-1-(3-(2-methylpropyl)-2-oxo-1,3,4-oxadiazolin-5-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.50 and 0.53 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 6.80 and 6.77 (each brd, J=9.0 Hz, 1H), 6.11 and 6.08(each brd, J=7.5 Hz, 1H), 5.34 and 5.28 (each m, 1H), 4.22–4.10 (m, 1H),3.76–3.70 (m, 4H), 3.70 (dd, J=14, 6.9 Hz, 1H), 3.63 (dd, J=14, 6.9 Hz,1H), 3.40 and 3.38 (each s, 2H), 2.79–2.70 (m, 1H), 2.57 (t, J=4.5 Hz,4H), 2.19 and 2.18 (each septet, J=6.9 Hz, 1H), 2.00–1.35 (m, 11H), 1.01(d, J=6.0 Hz, 3H), 1.00 (d, J=6.9 Hz, 6H), 0.98 and 0.97 (each d, J=6.0Hz, 3H).

REFERENCE EXAMPLE 19((4S)-2,2-dimethyl-3-t-butoxycarbonyl-4-(2-methylpropyl)-1,3-oxazolidin-5-yl)carboxylicAcid Methyl Ester

To a solution of(3S)-3-(N-t-butoxycarbonylamino)-5-methyl-2-hydroxyheptanoic acid methylester (4.40 g) in N,N-dimethylformamide (16 ml) was addedmethyl-2-propenyl ether (4.60 ml) and further was added dl-camphorsulfonic acid (186 mg) and the mixture was stirred overnight at roomtemperature. The residue was purified by column chromatography on silicagel (n-hexane:ethyl acetate=10:1 to 4:1) to give the title compound(3.90 g) having the following physical data.

TLC: Rf 0.52 and 0.48 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 4.61 and 4.44–4.12 (d and m, J=5.1 Hz, totally 2H), 3.78(s, 3H), 1.70–1.30 (m, 9H), 1.48 and 1.47 (each s, totally 9H),1.05–0.87 (m, 6H).

REFERENCE EXAMPLE 20((4S)-2,2-dimethyl-3-t-butoxycarbonyl-4-(2-methylpropyl)-1,3-oxazolidin-5-yl)carboxylicAcid

To a solution of the compound prepared in Reference Example 19 (3.84 g)in ethanol (12 ml)-water (6 ml) was added lithium hydroxide monohydrate(559 mg) and the mixture was stirred for 2 hours at room temperature. Tothe mixture was added n-hexane and the aqueous layer was collected. Tothe aqueous layer was added 1N hydrochloric acid and was extracted withethyl acetate. The extract was washed with saturated aqueous solution ofsodium chloride, dried over anhydrous magnesium sulfate and wasconcentrated to give a crude product of the title compound (3.82 g)having the following physical data.

NMR (CDCl₃): δ 4.45–4.22 (m, 2H), 1.85–1.30 (m, 3H), 1.66 and 1.58 (eachs, totally 6H), 1.48 (s, 9H), 1.04–0.85 (m, 6H).

REFERENCE EXAMPLE 21N-[(4S)-3-t-butoxycarbonyl-2,2-dimethyl-4-(2-methylpropyl)-1,3-oxazolidin-5-ylcarbonyl]-N′-phenylhydrazide

To a solution of the compound prepared in Reference Example 20 (3.81 g)in N,N-dimethylformamide (60 ml) were added 1-hydroxybenzotriazole (2.22g), phenylhydrazine (1.79 ml) and1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (2.78 g)successively at 0° C. and the mixture was stirred for 3 hours. Thereaction mixture was poured into 0.5N hydrochloric acid and wasextracted with ethyl acetate. The extract was washed with a saturatedaqueous solution of sodium bicarbonate and saturated aqueous solution ofsodium chloride successively, dried over anhydrous magnesium sulfate andconcentrated to give a crude product of the title compound (4.39 g)having the following physical data.

TLC: Rf 0.44, 0.29 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 8.28–8.16 (m, 1H), 7.28–7.19 (m, 2H), 6.97–6.81 (m, 3H),4.63 and 4.39 (each d, J=5.1 and 2.4 Hz), 4.42–4.30 (m, 1H), 1.76–1.30(m, 9H), 1.48 and 1.47 (each s, totally 9H), 1.01–0.85 (m, 6H).

REFERENCE EXAMPLE 222-(3-t-butoxycarbonyl-2,2-dimethyl-4-(2-methylpropyl)-1,3-oxazolidin-5-yl)₃-phenyl-2-oxo-(1,3,4-oxadiazoline)

To a solution of the compound prepared in Reference Example 21 (4.36 g)in tetrahydrofuran (110 ml) were added triethylamine (4.64 ml) and1,1-carbonyldiimidazole (9.00 g) successively and the mixture wasrefluxed overnight. The reaction mixture was concentrated and theresidue was diluted with ethyl acetate. The solution was poured into0.5N hydrochloric acid and was extracted with ethyl acetate. The extractwas washed with a saturated aqueous solution of sodium bicarbonate andsaturated aqueous solution of sodium chloride successively, dried overanhydrous magnesium sulfate and was concentrated to give a crude productof the title compound (3.32 g) having the following physical data.

TLC: Rf 0.45, 0.39 (n-hexane:ethyl acetate=4:1);

NMR (CDCl₃): δ 7.89–7.81 (m, 2H), 7.49–7.41 (m, 2H), 7.32–7.24 (m, 1H),5.05 (d, J=8.7 Hz, 0.5H), 4.81 (d, J=2.1 Hz, 0.5H), 4.60–4.15 (br, 1H),1.90–1.30 (m, 9H), 1.50 (s, 9H), 0.99, 0.93 and 0.86 (each d, J=6.0 Hz,totally 6H).

REFERENCE EXAMPLE 23(2S)-2-amino-4-methyl-1-(2-oxo-3-phenyl-1,3,4-oxadiazolin-5-yl)pentanolTosylate

To a solution of the compound prepared in Reference Example 22 (1.26 g)in ethanol (30 ml) was added p-toluene tosyl acid monohydrate (800 mg)and the mixture was refluxed for 3 hours. The reaction mixture wasconcentrated. The residue was washed with diethyl ether to give a crudeproduct of the title compound (1.24 g) having the following physicaldata.

TLC: Rf 0.22 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 8.12–7.87 (br, 3H), 7.81–7.73 (m, 2H), 7.56–7.44 (m, 4H),7.36–7.29 (m, 1H), 7.10 (d, J=8.7 Hz, 2H), 4.85 and 4.79 (each d, J=4.2Hz, totally 1H), 3.54–3.35 (br, 1H), 2.27 (s, 3H), 1.84–1.68 (m, 1H),1.64–1.44 (m, 2H), 1.00–0.82 (m, 6H).

EXAMPLE 11 TO EXAMPLE 11 (1)

By the same procedure as described in Reference Example 11→Example 1,using the compound prepared in Reference Example 23 andN-benzyloxycarbonyl-(L)-leucine or(1R,2S)-2-benzoylaminocyclohexylcarboxylic acid in place of the compoundprepared in Reference Example 10, the compounds of the present inventionhaving the following physical data were obtained.

EXAMPLE 111-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-phenyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.27 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.90–7.84 (m, 2H), 7.82–7.73 (m, 2H), 7.53–7.31 (m, 6H),7.12 (d, J=8.1 Hz, 1H), 6.35–6.15 (m, 1H), 5.50–5.32 (m, 1H), 4.44–4.28(m, 1H), 2.92–2.82 (m, 1H), 2.17–1.36 (m, 1H), 0.94 and 0.87 (each d,J=6.0 Hz, totally 6H).

EXAMPLE 11 (1)(2S)-N-[(2S)-4-methyl-1-oxo-1-(3-phenyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.62 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.88 (d, J=8.1 Hz, 2H), 7.50 (t, J=8.1 Hz, 2H), 7.44–7.20(m, 6H), 6.80–6.48 (m, 1H), 5.49–5.37 (m, 1H), 5.25–4.95 (m, 1H), 5.12(s, 2H), 4.32–4.11 (m, 1H), 1.85–1.35 (m, 6H), 1.10–0.85 (m, 12H).

EXAMPLE 121-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[(2S)-4-methyl-1-oxo-1-(3-carboxymethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]carboxamide

To the compound prepared in Example 10 (96) was added a 90% aqueoussolution of trifluoroacetic acid and the mixture was stirred for 1 hourat room temperature. The reaction mixture was concentrated to give thecompound of the present invention having the following physical data.

TLC: Rf 0.61 (chloroform:methanol:acetic acid=8:2:1);

NMR (DMSO-d₆): δ 8.39 (d, J=6.6 Hz, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.75(d, J=8.1 Hz, 2H), 7.53–7.37 (m, 3H), 4.89 (q, J=6.9 Hz, 1H), 4.62 (s,2H), 4.29–4.16 (m, 1H), 2.81–2.69 (m, 1H), 2.09–1.81 (m, 2H), 1.70–1.21(m, 9H), 0.73 and 0.66 (each d, J=6.0 Hz, totally 6H).

EXAMPLE 12 (1)(2S)-N-[(2S)-4-methyl-1-oxo-1-(3-carboxymethyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

By the same procedure as described in Example 12 using the compoundprepared in Example 10 (97) in place of the compound prepared in Example10 (96), the compound of the present invention having the followingphysical data was obtained.

TLC: Rf 0.65 (chloroform:methanol:acetic acid=8:2:1 );

NMR (DMSO-d₆): δ 8.49 (d, J=6.6 Hz, 1H), 7.45–7.23 (m, 5H), 7.39 (d,J=8.1 Hz, 1H), 5.00 (s, 2H), 4.96–4.85 (m, 1H), 4.68 (s, 2H), 4.12–4.00(m, 1H), 1.77–1.29 (m, 6H), 1.00–0.72 (m, 12H).

EXAMPLE 13 TO EXAMPLE 13 (121)

By the same procedure as described in Reference Example 15→Example 3using the compound prepared in Reference Example 14 or a correspondingamino derivative and N-benzyloxycarbonyl-(L)-leucine or a correspondingcarboxylic acid derivative and optionally converted into correspondingsalts by known methods, the compounds of the present invention havingthe following physical data were obtained.

EXAMPLE 131-[(1R,2S)-2-(quinoxalin-2-ylcarbonylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.23 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 9.65 (s, 1H), 8.62 (d, J=9.2 Hz, 1H), 8.25–8.10 (m, 2H),7.90–7.80 (m, 2H), 6.30 (d, J=7.8 Hz, 1H), 5.50–5.30 (m, 1H), 4.55–4.35(m, 1H), 2.92 (q, J=5.0 Hz, 1H), 2.77 (s, 3H), 2.30–1.40 (m, 11H), 0.79(d, J=6.6 Hz, 3H), 0.71 (d, J=6.2 Hz, 3H).

EXAMPLE 13 (1)1-[(1R,2S)-2-(naphthalen-2-ylcarbonylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.33 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 8.29 (s, 1H), 8.00–7.80 (m, 4H), 7.65–7.50 (m, 2H), 7.34(d, J=8.0 Hz, 1H), 6.33 (d, J=7.6 Hz, 1H), 5.50–5.35 (m, 1H), 4.50–4.35(m, 1H), 2.92 (q, J=4.9 Hz, 1H), 2.78 (s, 3H), 2.25–1.40 (m, 11H), 0.88(d, J=6.2 Hz, 3H), 0.81 (d, J=6.2 Hz, 3H).

EXAMPLE 13 (2)1-[(1R,2S)-2-(benzo[b]thiophen-2-ylcarbonylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.40 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.90–7.75 (m, 2H), 7.73 (s, 1H), 7.50–7.35 (m, 2H), 7.32(d, J=8.4 Hz, 1H), 6.30 (d, J=7.8 Hz, 1H), 5.50–5.35 (m, 1H), 4.40–4.20(m, 1H), 2.88 (q, J=4.8 Hz, 1H), 2.79 (s, 3H), 2.20–1.40 (m, 11H), 0.92(d, J=6.2 Hz, 3H), 0.85 (d, J=6.4 Hz, 3H).

EXAMPLE 13 (3)1-[(1R,2S)-2-(4-methoxybenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.21 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.73 (d, J=8.8 Hz, 2H), 7.07 (d, J=8.4 Hz, 1H), 6.92 (d,J=8.8 Hz, 2H), 6.29 (d, J=7.6 Hz, 1H), 5.50–5.35 (m, 1H), 4.40–4.20 (m,1H), 3.85 (s, 3H), 2.85 (q, J=5.0 Hz, 1H), 2.79 (s, 3H), 2.20–1.40 (m,1H), 0.91 (d, J=6.2 Hz, 3H), 0.85 (d, J=6.4 Hz, 3H).

EXAMPLE 13 (4)1-[(1R,2S)-2-(4-nitrobenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.33 (n-hexane ethyl acetate=1:1);

NMR (CDCl₃): δ 8.28 (d, J=9.0 Hz, 2H), 7.94 (d, J=9.0 Hz, 2H), 7.67 (d,J=7.6 Hz, 1H), 6.25 (d, J=7.6 Hz, 1H), 5.50–5.35 (m, 1H), 4.40–4.20 (m,1H), 2.85 (q, J=4.8 Hz, 1H), 2.81 (s, 3H), 2.10–1.40 (m, 11H), 0.96 (d,J=6.4 Hz, 3H), 0.91 (d, J=6.0 Hz, 3H).

EXAMPLE 13 (5)1-[(1R,2S)-2-(4-chlorobenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.36 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.71 (d, J=8.6 Hz, 2H), 7.40 (d, J=8.6 Hz, 2H), 7.30 (d,J=8.0 Hz, 1H), 6.25 (d, J=7.6 Hz, 1H), 5.50–5.35 (m, 1H), 4.35–4.20 (m,1H), 2.84 (q, J=5.0 Hz, 1H), 2.80 (s, 3H), 2.10–1.40 (m, 11H), 0.93 (d,J=6.2 Hz, 3H), 0.88 (d, J=6.2 Hz, 3H).

EXAMPLE 13 (6)1-[(1R,2S)-2-(4-phenylbenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.30 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.84 (d, J=8.7 Hz, 2H), 7.70–7.55 (m, 4H), 7.50–7.30 (m,3H), 7.30–7.20 (m, 1H), 6.27 (d, J=7.5 Hz, 1H), 5.50–5.30 (m, 1H),4.40–4.25 (m, 1H), 2.88 (q, J=4.9 Hz, 1H), 2.79 (s, 3H), 2.15–1.40 (m,11H), 0.93 (d, J=6.3 Hz, 3H), 0.86 (d, J=6.3 Hz, 3H).

EXAMPLE 13 (7)1-[(1R,2S)-2-(4-fluorobenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.32 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.78 (dd, J=8.8, 5.0 Hz, 2H), 7.30–7.15 (m, 1H), 7.10 (t,J=8.8 Hz, 2H), 6.27 (d, J=7.4 Hz, 1H), 5.50–5.35 (m, 1H), 4.40–4.20 (m,1H), 2.85 (q, J=4.8 Hz, 1H), 2.80 (s, 3H), 2.15–1.40 (m, 11H), 0.93 (d,J=6.6 Hz, 3H), 0.87 (d, J=6.4 Hz, 3H).

EXAMPLE 13 (8)1-[(1R,2S)-2-(pyridin-2-ylcarbonylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.21 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 8.70–8.55 (m, 2H), 8.16 (d, J=8.8 Hz, 1H), 7.84 (dt,J=1.4, 8.8 Hz, 1H), 7.43 (ddd, J=8.8, 4.8, 1.4 Hz, 1H), 6.42 (d, J=7.0Hz, 1H), 5.45–5.30 (m, 1H), 4.55–4.35 (m, 1H), 2.83 (q, J=5.3 Hz, 1H),2.78 (s, 3H), 2.20–1.40 (m, 11H), 0.82 (d, J=6.4 Hz, 3H), 0.75 (d, J=6.2Hz, 3H).

EXAMPLE 13 (9)1-[(1R,2S)-2-(4-t-butylbenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.36 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.70 (d, J=8.8 Hz, 2H), 7.44 (d, J=8.8 Hz, 2H), 7.12 (d,J=8.0 Hz, 1H), 6.28 (d, J=7.6 Hz, 1H), 5.50–5.35 (m, 1H), 4.40–4.25 (m,1H), 2.86 (q, J=4.9 Hz, 1H), 2.79 (s, 3H), 2.20–1.40 (m, 11H), 1.33 (s,9H), 0.90 (d, J=6.2 Hz, 3H), 0.84 (d, J=6.0 Hz, 3H).

EXAMPLE 13 (10)1-[(1R,2S)-2-(2-methylthiopyridin-3-ylcarbonylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.23 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 8.50 (dd, J=8.2, 1.8 Hz, 1H), 7.73 (dd, J=5.3, 1.8 Hz,1H), 7.17 (d, J=8.0 Hz, 1H), 7.04 (dd, J=8.2, 5.3 Hz, 1H), 6.28 (d,J=7.2 Hz, 1H), 5.45–5.30 (m, 1H), 4.45–4.30 (m, 1H), 2.86 (q, J=5.0 Hz,1H), 2.79 (s, 3H), 2.56 (s, 3H), 2.20–1.40 (m, 11H), 0.94 (d, J=6.2 Hz,3H), 0.90 (d, J=6.2 Hz, 3H).

EXAMPLE 13 (11)1-[(1R,2S)-2-(2-fluorobenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.37 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 8.04 (dt, J=2.0, 7.6 Hz, 1H), 7.55–7.40 (m, 2H), 7.24(dt, J=1.1, 7.6 Hz, 1H), 7.11 (ddd, J=12.0, 8.4, 1.1 Hz, 1H), 6.32 (d,J=7.4 Hz, 1H), 5.50–5.30 (m, 1H), 4.55–4.35 (m, 1H), 2.85 (q, J=4.9 Hz,1H), 2.79 (s, 3H), 2.20–1.40 (m, 11H), 0.90 (d, J=6.4 Hz, 3H), 0.82 (d,J=6.4 Hz, 3H).

EXAMPLE 13 (12)1-[(1R,2S)-2-(2-chloropyridin-5-ylcarbonylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.26 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 8.78 (d, J=2.2 Hz, 1H), 8.02 (dd, J=8.4, 2.2 Hz, 1H),7.58 (d, J=8.0 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 6.24 (d, J=7.4 Hz, 1H),5.50–5.35 (m, 1H), 4.35–4.20 (m, 1H), 2.83 (q, J=4.9 Hz, 1H), 2.80 (s,3H), 2.10–1.40 (m, 11H), 0.96 (d, J=6.2 Hz, 3H), 0.92 (d, J=6.2 Hz, 3H).

EXAMPLE 13 (13)1-[(1R,2S)-2-(naphthalen-1-ylmethylcarbonylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.22 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 8.00–7.75 (m, 3H), 7.60–7.35 (m, 4H), 6.30 (d, J=8.4 Hz,1H), 6.15 (d, J=6.6 Hz, 1H), 5.25–5.10 (m, 1H), 4.25–4.05 (m, 1H), 4.01(d, J=16.4 Hz, 1H), 3.95 (d, J=16.4 Hz, 1H), 2.80 (s, 3H), 2.51 (dt,J=6.6, 4.4 Hz, 1H), 1.80–1.10 (m, 11H), 1.00 (d, J=6.0 Hz, 3H), 0.98 (d,J=6.0 Hz, 3H).

EXAMPLE 13 (14)1-[(1R,2S)-2-benzylcarbonylaminocyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.22 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.40–7.20 (m, 5H), 6.34 (d, J=8.8 Hz, 1H), 6.23 (d, J=7.2Hz, 1H), 5.40–5.25 (m, 1H), 4.20–4.05 (m, 1H), 3.52 (s, 2H), 2.80 (s,3H), 2.65 (q, J=5.0 Hz, 1H), 1.95–1.30 (m, 11H), 1.02 (d, J=6.2 Hz, 3H),0.98 (d, J=6.0 Hz, 3H).

EXAMPLE 13 (15)1-[(1R,2S)-2-phenethylcarbonylaminocyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.24 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.35–7.10 (m, 5H), 6.30 (d, J=8.0 Hz, 1H), 6.21 (d, J=7.0Hz, 1H), 5.45–5.30 (m, 1H), 4.20–4.05 (m, 1H), 2.93 (t, J=7.5 Hz, 2H),2.79 (s, 3H), 2.65 (q, J=5.0 Hz, 1H), 2.50–2.40 (m, 2H), 1.90–1.30 (m,11H), 1.01 (d, J=6.4 Hz, 3H), 0.97 (d, J=6.2 Hz, 3H).

EXAMPLE 13 (16)1-[(1R,2S)-2-acetylaminocyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.61 (chloroform:methanol=9:1);

NMR (CDCl₃) δ 6.37 (d, J=8.8 Hz, 1H), 6.25 (d, J=7.0 Hz, 1H), 5.50–5.30(m, 1H), 4.20–4.05 (m, 1H), 2.80 (s, 3H), 2.74 (q, J=5.1 Hz, 1H),2.00–1.30 (m, 11H), 1.95 (s, 3H), 1.03 (d, J=6.2 Hz, 3H), 0.98 (d, J=6.2Hz, 3H).

EXAMPLE 13 (17)1-[(2S)-N-phenethylpiperidin-2-yl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.44 (chloroform:methanol=49:1);

NMR (CDCl₃): δ 7.30–7.10 (m, 5H), 6.75 (d, J=7.0 Hz, 1H), 5.40–5.20 (m,1H), 3.35 (br-d, J=11.6 Hz, 1H), 3.15–2.65 (m, 4H), 2.79 (s, 3H),2.60–1.10 (m, 11H), 0.97 (d, J=6.6 Hz, 3H), 0.93 (d, J=6.4 Hz, 3H).

EXAMPLE 13 (18)1-[(2S)-N-(3-phenylpropyl)piperidin-2-yl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.40 (chloroform:methanol=49:1);

NMR (CDCl₃): δ 7.35–7.10 (m, 6H), 5.55–5.35 (m, 1H), 3.14 (br-d, J=11.4Hz, 1H), 2.85–2.45 (m, 4H), 2.79 (s, 3H), 2.35–1.10 (m, 13H), 1.05 (d,J=6.2 Hz, 3H), 0.98 (d, J=6.2 Hz, 3H).

EXAMPLE 13 (19)1-[(2S)-N-(4-phenylbutyl)piperidin-2-yl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.38 (chloroform methanol=49:1);

NMR (CDCl₃) δ 7.35–7.10 (m, 6H), 5.50–5.35 (m, 1H), 3.11 (br-d, J=11.6Hz, 1H), 2.85–2.45 (m, 4H), 2.78 (s, 3H), 2.35–1.15 (m, 15H), 1.05–0.80(m, 6H).

EXAMPLE 13 (20)1-[(2S)-N-phenethylpiperidin-2-yl]-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.51 (chloroform:methanol=49:1);

NMR (CDCl₃): δ 7.35–7.10 (m, 5H), 6.74 (d, J=7.5 Hz, 1H), 5.40–5.25 (m,1H), 4.03 (septet, J=6.9 Hz, 1H), 3.40–3.20 (m, 1H), 3.10–2.70 (m, 4H),2.60–1.10 (m, 11H), 1.53 (d, J=6.9 Hz, 6H), 0.97 (d, J=6.3 Hz, 3H), 0.92(d, J=6.3 Hz, 3H).

EXAMPLE 13 (21)1-[(2S)-N-(3-phenylpropyl)piperidin-2-yl]-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.41 (chloroform:methanol=49:1);

NMR (CDCl₃): δ 7.35–7.10 (m, 6H), 5.55–5.40 (m, 1H), 4.04 (septet, J=6.7Hz, 1H), 3.14 (br-d, J=11.4 Hz, 1H), 2.80–2.50 (m, 4H), 2.30–1.00 (m,13H), 1.54 (d, J=6.7 Hz, 6H), 1.05 (d, J=6.3 Hz, 3H), 0.98 (d, J=6.3 Hz,3H).

EXAMPLE 13 (22)1-[(1R,2S)-2-(4-cyanobenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.30 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃) δ 7.87 (d, J=8.0 Hz, 2H), 7.73 (d, J=8.0 Hz, 2H), 7.60 (d,J=8.4 Hz, 1H), 6.25 (d, J=7.8 Hz, 1H), 5.50–5.35 (m, 1H), 4.35–4.20 (m,1H), 2.85 (q, J=5.0 Hz, 1H), 2.80 (s, 3H), 2.10–1.40 (m, 11H), 0.95 (d,J=6.3 Hz, 3H), 0.91 (d, J=6.6 Hz, 3H).

EXAMPLE 13 (23)1-[(1R,2S)-2-(4-dimethylaminobenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

Free Compound

TLC: RF 0.62 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.66 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.0 Hz, 1H), 6.67 (d,J=8.8 Hz, 2H), 6.41 (d, J=7.4 Hz, 1H), 5.50–5.30 (m, 1H), 4.40–4.25 (m,1H), 3.02 (s, 6H), 2.90–2.75 (m, 1H), 2.79 (s, 3H), 2.15–1.35 (m, 11H),0.90 (d, J=6.4 Hz, 3H), 0.84 (d, J=6.0 Hz, 3H).

Hydrochloride

TLC: Rf 0.62 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.89 (d, J=8.4 Hz, 2H), 7.66 (d, J=8.4 Hz, 2H), 7.50 (d,J=7.8 Hz, 1H), 6.35 (d, J=7.4 Hz, 1H), 5.50–5.30 (m, 1H), 4.40–4.20 (m,1H), 3.16 (s, 6H), 2.90–2.75 (m, 1H), 2.80 (s, 3H), 2.10–1.30 (m, 11H),0.94 (d, J=6.2 Hz, 3H), 0.90 (d, J=6.2 Hz, 3H).

EXAMPLE 13 (24)1-[(1R,2S)-2-(4-fluorobenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.48 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.78 (dd, J=8.8, 5.0 Hz, 2H), 7.30–7.20 (m, 1H), 7.10 (t,J=8.8 Hz, 2H), 6.28 (d, J=7.6 Hz, 1H), 5.50–5.35 (m, 1H), 4.35–4.20 (m,1H), 4.05 (septet, J=6.8 Hz, 1H), 2.85 (q, J=5.0 Hz, 1H), 2.20–1.30 (m,11H), 1.54 (d, J=6.8 Hz, 6H), 0.93 (d, J=6.2 Hz, 3H), 0.87 (d, J=6.2 Hz,3H).

EXAMPLE 13 (25)1-[(1R,2S)-2-(4-chlorobenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.56 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.71 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 7.31 (d,J=6.8 Hz, 1H), 6.23 (d, J=7.8 Hz, 1H), 5.50–5.35 (m, 1H), 4.35–4.20 (m,1H), 4.05 (septet, J=6.8 Hz, 1H), 2.84 (q, J=4.9 Hz, 1H), 2.15–1.30 (m,11H), 1.55 (d, J=6.8 Hz, 6H), 0.94 (d, J=6.4 Hz, 3H), 0.88 (d, J=6.2 Hz,3H).

EXAMPLE 13 (26)1-[(1R,2S)-2-(4-methoxybenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf0.35 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.73 (d, J=8.8 Hz, 2H), 7.08 (d, J=8.0 Hz, 1H), 6.92 (d,J=8.8 Hz, 2H), 6.28 (d, J=7.8 Hz, 1H), 5.50–5.35 (m, 1H), 4.40–4.20 (m,1H), 4.04 (septet, J=7.0 Hz, 1H), 3.85 (s, 3H), 2.85 (q, J=4.9 Hz, 1H),2.20–1.35 (m, 11H), 1.54 (d, J=7.0 Hz, 1H), 0.91 (d, J=6.2 Hz, 3H), 0.85(d, J=6.4 Hz, 3H).

EXAMPLE 13 (27)1-[(1R,2S)-2-(4-cyanobenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.48 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.88 (d, J=8.5 Hz, 2H), 7.73 (d, J=8.5 Hz, 2H), 7.61 (d,J=7.8 Hz, 1H), 6.23 (d, J=7.8 Hz, 1H), 5.55–5.35 (m, 1H), 4.35–4.20 (m,1H), 4.05 (septet, J=6.8 Hz, 1H), 2.84 (q, J=4.9 Hz, 1H), 2.10–1.30 (m,11H), 1.55 (d, J=6.8 Hz, 6H), 0.95 (d, J=6.2 Hz, 3H), 0.91 (d, J=6.2 Hz,3H).

EXAMPLE 13 (28)1-[(1R,2S)-2-(4-dimethylaminobenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

Free Compound

TLC: Rf 0.25 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.66 (d, J=9.2 Hz, 2H), 6.88 (d, J=8.0 Hz, 1H), 6.66 (d,J=9.2 Hz, 2H), 6.36 (d, J=7.4 Hz, 1H), 5.50–5.35 (m, 1H), 4.45–4.25 (m,1H), 4.04 (septet, J=6.6 Hz, 1H), 3.02 (s, 6H), 2.85 (q, J=5.1 Hz, 1H),2.15–1.40 (m, 11H), 1.54 (d, J=6.6 Hz, 6H), 0.90 (d, J=6.2 Hz, 3H), 0.84(d, J=6.2 Hz, 3H).

Hydrochloride

TLC: Rf 0.25 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃) δ 7.92 (d, J=8.8 Hz, 2H), 7.77 (d, J=8.8 Hz, 2H), 7.56 (d,J=8.0 Hz, 1H), 6.31 (d, J=7.8 Hz, 1H), 5.50–5.35 (m, 1H), 4.35–4.20 (m,1H), 4.05 (septet, J=6.8 Hz, 1H), 3.18 (s, 6H), 2.84 (q, J=4.9 Hz, 1H),2.10–1.40 (m, 11H), 1.55 (d, J=6.8 Hz, 6H), 0.95 (d, J=6.2 Hz, 3H), 0.91(d, J=6.2 Hz, 3H).

EXAMPLE 13 (29)1-[(1R,2S)-2-(N-benzoyl-N-methylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.33 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.45–7.29 (m, 5H), 6.50–6.27 (br, 1H), 5.43–5.31 (m, 1H),4.61–4.30 (br, 1H), 3.36–3.00 (br, 1H), 2.87 (s, 3H), 2.78 (s, 3H),2.60–2.36 (m, 1H), 2.02–1.23 (m, 10H), 0.94 and 0.90 (each d, J=6.2 Hz,each 3H).

EXAMPLE 13 (30) 1-[(1R,2S)-2-(4-dimethylaminomethylbenzoylamino)cyclohexyl]-N-[4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

Free Compound

TLC: Rf 0.44 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.66 and 7.72 (each d, J=8.4 Hz, totally 2H), 7.37 and7.35 (each d, J=8.4 Hz, totally 2H), 7.24 and 7.16 (each d, J=8.0 Hz,totally 1H), 6.33 and 6.29 (each d, J=8.0 Hz, totally 1H), 5.50–5.30 (m,1H), 4.40–4.25 (m, 1H), 4.05 and 4.03 (each septet, J=6.8 Hz, totally1H), 3.47 and 3.46 (each s, totally 2H), 2.90–2.80 (m, 1H), 2.24 and2.23 (each s, totally 6H), 2.20–1.40 (m, 11H), 1.54 and 1.53 (each d,J=6.8 Hz, totally 6H), 1.02, 0.94, 0.91 and 0.85 (each d, J=5.8, 5.8,6.2 and 6.2 Hz, totally 6H).

Hydrochloride

TLC: Rf 0.44 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.85 and 7.84 (each d, J=8.2 Hz, totally 2H), 7.68 and7.64 (each d, J=8.2 Hz, totally 2H), 7.47 and 7.35 (each d, J=8.0 and8.8 Hz, totally 1H), 6.78 and 6.37 (each d, J=7.0 and 7.8 Hz, totally1H), 5.50–5.30 (m, 1H), 4.31 (br, 1H), 4.23 and 4.20 (each s, totally2H), 4.05 (septet, J=6.8 Hz, 1H), 3.00–2.85 (m, 1H), 2.75 and 2.74 (eachs, totally 6H), 2.10–1.40 (m, 1H), 1.54 (d, J=6.8 Hz, 6H), 1.04, 0.97,0.94 and 0.90 (each d, J=6.0, 6.0, 6.2 and 6.2 Hz, totally 6H).

EXAMPLE 13 (31)1-[(1R,2S)-2-(2-aminopyridin-5-ylcarbonylamino)cyclohexyl]-N-[4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.37 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 8.56 and 8.52 (each d, J=2.2 Hz, totally 1H), 7.84 and7.81 (each dd, J=8.6, 2.2 Hz, totally 1H), 7.15–7.00 (m, 1H), 6.48 (d,J=8.6 Hz, 1H), 6.45–6.30 (m, 1H), 5.50–5.30 (m, 1H), 4.84 (br, 2H),4.40–4.20 (m, 1H), 4.04 (septet, J=6.6 Hz, 1H), 2.90–2.75 (m, 1H),2.20–1.30 (m, 11H), 1.54 (d, J=6.6 Hz, 6H), 1.02, 0.95, 0.93 and 0.87(each d, J=5.8, 6.0, 6.2 and 6.2 Hz, totally 6H).

EXAMPLE 13 (32)1-[(1R,2S)-2-(2-aminopyridin-5-ylcarbonylamino)cyclohexyl]-N-[4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.42 (chloroform methanol=9:1);

NMR (CDCl₃): δ 8.55 and 8.52 (each d, J=2.4 Hz, totally 1H), 7.85 and7.81 (each dd, J=8.8, 2.4 Hz, totally 1H), 7.07 (d, J=7.4 Hz, 1H),6.55–6.35 (m, 2H), 5.50–5.30 (m, 1H), 4.88 (br, 2H), 4.40–4.20 (m, 1H),2.90–2.75 (m, 1H), 2.79 and 2.78 (each s, totally 3H), 2.10–1.30 (m,11H), 1.02, 0.95, 0.92 and 0.87 (each d, J=6.0, 6.2, 6.2 and 6.2 Hz,totally 6H).

EXAMPLE 13 (33)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[(2S)-4-methyl-1-(5-t-butoxycarbonylmethylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.54 (n-hexane:ethyl acetate=1:2);

NMR (CDCl₃): δ 7.80–7.73 (m, 2H), 7.53–7.38 (m, 3H), 7.20 (brd, J=8.4Hz, 1H), 6.26 (d, J=7.8 Hz, 1H), 5.46–5.36 (m, 1H), 4.37–4.27 (m, 1H),4.06 (s, 2H), 2.86 (q, J=4.8 Hz, 1H), 2.15–1.30 (m, 11H), 1.49 (s, 9H),0.90 and 0.85 (each d, J=6.3 Hz, totally 6H).

EXAMPLE 13 (34)(2S)-N-[(2S)-4-methyl-1-(5-t-butoxycarbonylmethylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]-4-methyl-2-benzyloxycarbonylaminopentanamide

TLC: Rf 0.53 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.45–7.24 (m, 5H), 6.64 (brd, J=6.6 Hz, 1H), 5.46–5.35(m, 1H), 5.23–5.06 (m, 3H), 4.32–4.18 (m, 1H), 4.06 (s, 2H), 1.86–1.41(m, 6H), 1.48 (s, 9H), 1.03–0.85 (m, 12H).

EXAMPLE 13 (35)1-[(1R,2S)-2-(4-dimethylaminomethylbenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.44 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.72 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.16 (d,J=8.1 Hz, 1H), 6.25 (d, J=7.8 Hz, 1H), 5.48–5.41 (m, 1H), 4.36–4.30 (m,1H), 4.09–4.00 (m, 1H), 3.48 (s, 2H), 2.89–2.84 (m, 1H), 2.25 (s, 6H),2.14–1.43 (m, 17H), 0.91 (d, J=6.6 Hz, 3H), 0.85 (d, J=6.6 Hz, 3H).

EXAMPLE 13 (36)1-[(1R,2S)-2-(4-dimethylaminomethylbenzoylamino)cyclohexyl]-N-[4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.35 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.76 and 7.72 (each d, J=8.0 and 8.4 Hz, totally 2H),7.37 and 7.35 (each d, J=8.0 and 8.4 Hz, totally 2H), 7.22 and 7.16(each d, J=8.4 and 8.0 Hz, totally 1H), 6.39 and 6.33 (each d, J=7.0 and7.6 Hz, totally 1H), 5.50–5.30 (m, 1H), 4.40–4.25 (m, 1H), 3.48 and 3.47(each s, totally 2H), 2.90–2.80 (m, 1H), 2.79 and 2.78 (each s, totally3H), 2.25 and 2.24 (each s, totally 6H), 2.20–1.40 (m, 11H), 1.01, 0.94,0.91 and 0.84 (each d, J=6.0, 6.0, 6.2 and 6.2 Hz, totally 6H).

EXAMPLE 13 (37)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[(2S)-4-methyl-1-(5-bis(methoxycarbonyl)methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.26 (n-hexane:ethyl acetate=1:2);

NMR (CDCl₃): δ 7.80–7.72 (m, 2H), 7.53–7.38 (m, 3H), 7.15 (brd, J=7.8Hz, 1H), 6.24 (d, J=7.5 Hz, 1H), 5.46–5.35 (m, 1H), 5.39 (s, 1H),4.39–4.27 (m, 1H), 3.87 (s, 6H), 2.86 (q, J=5.4 Hz, 1H), 2.14–1.40 (m,11H), 0.90 and 0.85 (each d, J=6.3 Hz, totally 6H).

EXAMPLE 13 (38)(2S)-N-[(2S)-4-methyl-1-(5-bis(methoxycarbonyl)methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]-4-methyl-2-benzyloxycarbonylaminopentanamide

TLC: Rf 0.49 (n-hexane:ethyl acetate=1:2);

NMR (CDCl₃): δ 7.45–7.26 (m, 5H), 6.74–6.56 (br, 1H), 5.44–5.34 (m, 1H),5.39 (s, 1H), 5.20–5.04 (m, 3H), 4.30–4.15 (m, 1H), 3.87 (s, 6H),1.87–1.40 (m, 6H), 1.04–0.83 (m, 12H).

EXAMPLE 13 (39)1-[(1R,2S)-2-(4-dimethylaminomethyl-2-fluorobenzoylamino)cyclohexyl]-N-[4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.57 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 8.02–7.90 (m, 1H), 7.50–7.38 (m, 1H), 7.22–7.05 (m, 2H),6.50 and 6.30 (each brd, J=7.5 Hz, totally 1H), 5.48–5.32 (m, 1H),4.52–4.39 (m, 1H), 4.10–3.93 (m, 1H), 3.43 (m, 2H), 2.88–2.75 (m, 1H),2.25 (s, 6H), 2.20–1.40 (m, 17H), 1.01, 0.95, 0.89, and 0.81 (each d,J=6.3 Hz, totally 6H).

EXAMPLE 13 (40)1-[(1R,2S)-2-(4-dimethylaminomethyl-2-fluorobenzoylamino)cyclohexyl]-N-[4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.37 (chloroform:methanol=9:1);

NMR (CDCl₃) δ 8.01–7.90 (m, 1H), 7.50–7.35 (m, 1H), 7.20–7.05 (m, 2H),6.55 and 6.35 (each brd, J=6.3 Hz, totally 1H), 5.48–5.30 (m, 1H),4.60–4.38 (m, 1H), 3.45 (m, 2H), 2.85 (m, 1H), 2.78 and 2.76 (each s,totally 3H), 2.25 (s, 6H), 2.20–1.40 (m, 11H), 1.05–0.80 (m, 6H).

EXAMPLE 13 (41)1-[(1R,2S)-2-benzoylaminocyclopentyl]-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.35 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.83–7.75 (m, 2H), 7.54–7.39 (m, 3H), 6.95 (brd, J=7.8Hz, 1H), 6.23 (brd, J=7.5 Hz, 1H), 5.43–5.33 (m, 1H), 4.71–4.58 (m, 1H),4.10–3.96 (m, 1H), 3.07 (q, J=7.5 Hz, 1H), 2.16–1.38 (m, 9H), 1.54 (d,J=6.9 Hz, 6H), 0.73 and 0.72 (each d, J=6.3 Hz, totally 6H).

EXAMPLE 13 (42)1-[(1R,2S)-2-benzoylaminocyclopentyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.20 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.82–7.72 (m, 2H), 7.54–7.39 (m, 3H), 6.94 (brd, J=7.5Hz, 1H), 6.23 (brd, J=7.5 Hz, 1H), 5.42–5.33 (m, 1H), 4.72–4.58 (m, 1H),3.07 (q, J=7.5 Hz, 1H), 2.79 (s, 3H), 2.15–1.37 (m, 9H), 0.73 and 0.72(each d, J=6.3 Hz, totally 6H).

EXAMPLE 13 (43)1-[(1R,2S)-2-(4-morpholinomethylbenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamideHydrochloride

TLC: Rf 0.63 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 8.47 (d, J=6.3 Hz, 1H), 7.88–7.82 (m, 3H), 7.66 (d,J=7.5 Hz, 2H), 5.07–5.00 (m, 1H), 4.39 (br-s, 2H), 4.27 (m, 1H),4.00–3.87 (m, 3H), 3.79–3.82 (m, 2H), 3.24–3.02 (m, 4H), 2.78–2.75 (m,1H), 2.04–1.84 (m, 2H), 1.67–1.22 (m, 9H), 1.45 (d, J=6.9 Hz, 6H), 0.77(d, J=6.0 Hz, 3H), 0.72 (d, J=6.0 Hz, 3H).

EXAMPLE 13 (44)1-[(1R,2S)-2-(4-pyrrolidinomethylbenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamideHydrochloride

TLC: Rf 0.48 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 8.63 and 8.46 (each d, J=6.6 Hz, totally 1H), 7.90–7.74(m, 3H), 7.67–7.63 (m, 2H), 5.04–4.88 (m, 1H), 4.38 (m, 2H), 4.30–4.11(m, 1H), 3.98–3.86 (m, 1H), 3.41–3.24 (m, 2H), 3.03 (m, 2H), 2.80–2.73(m, 1H), 2.00–1.88 (m, 6H), 1.68–1.22 (m, 15H), 0.86, 0.82, 0.76, and0.71 (each d, J=5.7 Hz, totally 6H).

EXAMPLE 13 (45)1-[(1R,2S)-2-(2-dimethylaminomethylbenzoylamino)cyclohexyl]-N-[4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.41 and 0.34 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 10.65–10.40 (m, 1H), 8.05–7.90 (m, 1H), 7.50–7.30 (m,2H), 7.25–7.10 (m, 1H), 7.05 and 6.36 (each d, J=6.6 Hz, totally 1H),5.35–5.20 (m, 1H), 4.53 and 4.34 (each br, totally 1H), 3.71, 3.53, 3.44and 3.40 (each d, J=12.0, 11.8, 11.8 and 12.0 Hz, totally 2H), 3.15–2.80(m, 1H), 2.77 and 2.74 (each s, totally 3H), 2.22 and 2.20 (each s,totally 6H), 2.20–1.30 (m, 11H), 0.97, 0.94, 0.72 and 0.70 (each d,J=6.2 Hz, totally 6H).

EXAMPLE 13 (46)1-[(1R,2S)-2-(2-dimethylaminomethylbenzoylamino)cyclohexyl]-N-[4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.43 and 0.36 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 10.65–10.40 (m, 1H), 8.05–7.90 (m, 1H), 7.45–7.30 (m,2H), 7.25–7.10 (m, 1H), 7.04 and 6.36 (each d, J=6.2 and 7.4 Hz, totally1H), 5.40–5.20 (m, 1H), 4.53 and 4.33 (each br, totally 1H), 4.02 and3.99 (each septet, J=6.8 Hz, totally 1H), 3.72, 3.53, 3.44 and 3.41(each d, J=12.2, 11.7, 11.7 and 12.2 Hz, totally 2H), 3.15–2.85 (m, 1H),2.22 and 2.21 (each s, totally 6H), 2.20–1.20 (m, 11H), 1.53 and 1.51(each d, J=6.8 Hz, totally 6H), 0.98, 0.94, 0.72 and 0.71 (each d, J=6.4Hz, totally 6H).

EXAMPLE 13 (47)1-[(1R,2S)-2-(3-dimethylaminomethylbenzoylamino)cyclohexyl]-N-[4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.44 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.75–7.60 (m, 2H), 7.50–7.30 (m, 2H), 7.21 and 7.16 (eachd, J=8.8 and 7.6 Hz, totally 1H), 6.42 and 6.35 (each d, J=7.8 and 7.4Hz, totally 1H), 5.50–5.30 (m, 1H), 4.40–4.25 (m, 1H), 3.47 (s, 2H),2.90–2.80 (m, 1H), 2.79 and 2.77 (each s, totally 3H), 2.25 and 2.23(each s, totally 6H), 2.20–1.35 (m, 11H), 1.01, 0.94, 0.89 and 0.84(each d, J=6.2 Hz, totally 6H).

EXAMPLE 13 (48) 1-[(1R,2S)-2-(3-dimethylaminomethylbenzoylamino)cyclohexyl]-N-[4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.40 (chloroform methanol=9:1);

NMR (CDCl₃): δ 7.75–7.60 (m, 2H), 7.50–7.30 (m, 2H), 7.21 and 7.17 (eachd, J=9.6 Hz, totally 1H), 6.43 and 6.35 (each d, J=7.0 and 7.4 Hz,totally 1H), 5.50–5.30 (m, 1H), 4.40–4.25 (m, 1H), 4.04 and 4.03 (eachseptet, J=6.7 Hz, totally 1H), 3.47 (s, 2H), 2.90–2.80 (m, 1H), 2.25 and2.24 (each s, totally 6H), 2.20–1.30 (m, 11H), 1.54 and 1.53 (each d,J=6.7 Hz, totally 6H), 1.02, 0.94, 0.90 and 0.84 (each d, J=6.2 Hz,totally 6H).

EXAMPLE 13 (49)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[1-(5-(2-dimethylaminoethylthio)-1,3,4-oxadiazol-2-yl)-4-methyl-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.24 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.82–7.71 (m, 2H), 7.51–7.38 (m, 3H), 7.24–7.18 (m, 1H),6.29 and 6.25 (each brd, J=7.5 Hz, totally 1H), 5.50–5.30 (m, 1H),4.42–4.30 (m, 1H), 3.51–3.40 (m, 2H), 2.90–2.82 (m, 1H), 2.80–2.70 (m,2H), 2.32 (s, 6H), 2.10–1.40 (m, 11H), 1.01, 0.94, 0.90 and 0.84 (eachd, J=6.3 Hz, totally 6H).

EXAMPLE 13 (50)1-[(1R,2S)-2-(4-morpholinomethylbenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamideHydrochloride

TLC: Rf 0.66 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 8.61 and 8.47 (each d, J=6.9 Hz, totally 1H), 7.87–7.81(m, 3H), 7.65 (d, J=7.8 Hz, 2H), 5.06–4.91 (m, 1H), 4.37 (br-s, 2H),4.30–4.12 (m, 1H), 3.95–3.91 (m, 2H), 3.81–3.73 (m, 2H), 3.26–3.00 (m,4H), 2.82–2.66 (m, 4H), 2.07–1.82 (m, 2H), 1.65–1.22 (m, 9H), 0.86,0.83, 0.77, and 0.72 (each d, J=6.3 Hz, totally 6H).

EXAMPLE 13 (51)1-[(1R,2S)-2-(4-pyrrolidinomethylbenzoylamino)cyclohexyl]-N-[4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.41 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.79 and 7.75 (each d, J=8.1 Hz, totally 2H), 7.51 (d,J=8.1 Hz, 2H), 7.29–7.23 (m, 1H), 6.39 and 6.28 (each d, J=7.5 Hz,totally 1H), 5.45–5.34 (m, 1H), 4.38–4.37 (m, 1H), 3.89 and 3.88 (eachs, totally 2H), 2.85–2.70 (m, 8H), 2.05–1.42 (m, 15H), 1.02, 0.95, 0.92,and 0.87 (each d, J=6.3 Hz, totally 6H).

EXAMPLE 13 (52)(2S)-N-[1-(5-(2-dimethylaminoethylthio)-1,3,4-oxadiazol-2-yl)-4-methyl-1-oxo-2-pentyl]-4-methyl-2-benzyloxycarbonylaminopentanamide

TLC: Rf 0.41 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.42–7.30 (m, 5H), 6.72 and 6.59 (each m, totally 1H),5.45–5.35 (m, 1H), 5.21–5.02 (m, 3H), 4.32–4.19 (m, 1H), 3.49 (t, J=5.7Hz, 2H), 2.75 (t, J=5.7 Hz, 2H), 2.31 (s, 6H), 1.90–1.41 (m, 6H),1.05–0.90 (m, 12H).

EXAMPLE 13 (53)1-[(1R,2S)-2-(2-dimethylaminomethyl-4-fluorobenzoylamino)cyclohexyl]-N-[4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf0.43 and 0.37 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 10.52–10.31 (m, 1H), 8.05–7.92 (m, 1H), 7.10–7.02 (m,1H), 6.90 (m, 1H), 6.90 and 6.28 (each br, totally 1H), 5.38–5.27 (m,1H), 4.50 and 4.30 (each m, totally 1H), 4.01 (septet, J=6.9 Hz, 1H),3.70–3.30 (m, 2H), 3.08 and 2.92 (each m, totally 1H), 2.30–2.20 (m,6H), 2.10–1.40 (m, 17H), 1.05–0.70 (m, 6H).

EXAMPLE 13 (54)(2S)-N-[3-cyclopropyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-propyl]-4-methyl-2-benzyloxycarbonylaminopentanamide

TLC: Rf 0.27 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 7.40–7.25 (m, 5H), 7.01 and 6.87 (br and d, J=6.6 Hz,totally 1H), 5.55–5.40 (m, 1H), 5.20–5.05 (m, 3H), 4.30–4.20 (m, 1H),2.79 and 2.78 (each s, totally 3H), 2.00–1.40 (m, 5H), 1.00–0.85 (m,6H), 0.80–0.60 (m, 1H), 0.50–0.35 (m, 2H), 0.15–0.05 (m, 2H).

EXAMPLE 13 (55)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[3-cyclopropyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-propyl]carboxamide

TLC: Rf 0.43 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.85–7.70 (m, 2H), 7.50–7.25 (m, 4H), 6.54 (d, J=6.6 Hz,1H), 5.55–5.40 (m, 1H), 4.40–4.25 (m, 1H), 2.87 (q, J=5.1 Hz, 1H), 2.79and 2.78 (each s, totally 3H), 2.10–1.40 (m, 10H), 0.70–0.55 (m, 1H),0.50–0.30 (m, 2H), 0.10–0.10 (m, 2H).

EXAMPLE 13 (56)1-[(1R,2S)-2-(2-dimethylaminomethyl-4-fluorobenzoylamino)cyclohexyl]-N-[4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.28 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.58–7.20 (m, 4H), 6.29 and 6.25 (each brd, J=7.8 Hz,totally 1H), 5.51–5.35 (m, 1H), 4.38–4.25 (m, 1H), 3.60–3.40 (m, 2H),2.90–2.70 (m, 4H), 2.32–1.39 (m, 11H), 1.05, 0.99, 0.97, and 0.88 (eachd, J=6.3 Hz, totally 6H).

EXAMPLE 13 (57)1-benzoylaminocyclohexyl-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.70 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 8.02 (d, J=6.6 Hz, 1H), 7.77 (d, J=6.9 Hz, 2H), 7.55 (t,J=6.9 Hz, 1H), 7.47 (t, J=6.9 Hz, 2H), 6.04 (brs, 1H), 5.38 (m, 1H),4.00 (septet, J=6.6 Hz, 1H), 2.28 (br, 2H), 2.00 (br, 2H), 1.90–1.21 (m,15H), 1.01 and 0.97 (each d, J=5.7 Hz, each 3H).

EXAMPLE 13 (58)1-[(1R,2S)-2-(3-morpholinomethylbenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamideHydrochloride

TLC: Rf 0.46 (chloroform:methanol=19:1);

NMR (DMSO-d₆): δ 8.46 (d, J=6.3 Hz, 1H), 8.01 (s, 1H), 7.82 (d, J=7.5Hz, 2H), 7.72 (d, J=7.2 Hz, 1H), 7.53 (t-like, J=7.5 Hz, 1H), 5.06–4.98(m, 1H), 4.39 (br-s, 2H), 4.29 (m, 1H), 3.95–3.91 (m, 2H), 3.77–3.69 (m,2H), 3.38–3.03 (m, 4H), 2.75 (s, 4H), 1.98–1.90 (m, 2H), 1.70–1.23 (m,9H), 0.77 (d, J=6.0 Hz, 3H), 0.72 (d, J=6.0 Hz, 3H).

EXAMPLE 13 (59)1-[(1R,2S)-2-(3-morpholinomethylbenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamideHydrochloride

TLC: Rf 0.49 (chloroform:methanol=19:1);

NMR (DMSO-d₆) δ 8.46 (d, J=6.3 Hz, 1H), 8.02 (s, 1H), 7.81 (d, J=7.5 Hz,2H), 7.73 (d, J=7.8 Hz, 1H), 7.53 (t-like, J=7.5 Hz, 1H), 5.06–4.99 (m,1H), 4.39 (br-s, 2H), 4.30 (m, 1H), 3.98–3.87 (m, 3H), 3.79–3.71 (m,2H), 3.41–3.03 (m, 4H), 2.76–2.73 (m, 1H), 2.02–1.90 (m, 2H), 1.67–1.22(m, 9H), 1.45 (d, J=6.6 Hz, 6H), 0.77 (d, J=6.0 Hz, 3H), 0.72 (d, J=6.0Hz, 3H).

EXAMPLE 13 (60)1-[(1R,2S)-2-(3-pyrrolidinomethylbenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamideHydrochloride

TLC: Rf 0.43 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 8.58 and 8.46 (each d, J=6.3 Hz, totally 1H), 7.99 and7.94 (each s, totally 1H), 7.80 (d, J=7.5 Hz, 2H), 7.74 and 7.67 (eachd, J=7.8 Hz, totally 1H), 7.52 (t-like, J=7.5 Hz, 1H), 5.06–4.98 (m,1H), 4.39 and 4.37 (each s, totally 2H), 4.29 (m, 1H), 3.41–3.26 (m,2H), 3.11–2.98 (m, 2H), 2.81–2.70 (m, 1H), 2.74 (s, 3H), 2.01–1.85 (m,7H), 1.61–1.22 (m, 8H), 0.86, 0.83, 0.77, and 0.71 (each d, J=6.3 Hz,totally 6H).

EXAMPLE 13 (61)1-[(1R,2S)-2-(3-pyrrolidinomethylbenzoylamino)cyclohexyl]-N-[4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamideHydrochloride

TLC: Rf 0.39 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 8.46 (each d, J=6.6 Hz, 1H), 7.98 (s, 1H), 7.81 (d,J=7.5 Hz, 2H), 7.72 (d, J=6.9 Hz, 1H), 7.52 (t-like, J=7.5 Hz, 1H),5.08–5.00 (m, 1H), 4.40 and 4.38 (each s, totally 2H), 4.29 (m, 1H),4.00–3.87 (m, 1H), 3.41–3.32 (m, 2H), 3.12–3.00 (m, 2H), 2.77–2.73 (m,1H), 2.01–1.85 (m, 7H), 1.68–1.23 (m, 8H), 1.45 (d, J=6.9 Hz, 6H) 0.77(d, J=5.1 Hz, 3H), 0.71 (d, J=5.1 Hz, 3H).

EXAMPLE 13 (62)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[2-(5-methylthio-1,3,4-oxadiazol-2-yl)-2-oxoethyl]carboxamide

TLC: Rf 0.38 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.82–7.74 (m, 2H), 7.51–7.38 (m, 3H), 7.31 (brd, J=8.7Hz, 1H), 6.53 (brt, J=5.4 Hz, 1H), 4.78 (dd, J=19.5, 5.1 Hz, 1H), 4.75(dd, J=19.5, 5.1 Hz, 1H), 4.42–4.31 (m, 1H), 2.93–2.87 (m, 1H), 2.79 (s,3H), 2.13–1.40 (m, 8H).

EXAMPLE 13 (63)(2S)-N-[2-(5-methylthio-1,3,4-oxadiazol-2-yl)-2-oxoethyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.53 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.45–7.26 (m, 5H), 6.82 (brs, 1H), 5.23–5.06 (m, 1H),5.13 (s, 2H), 4.85–4.73 (m, 2H), 4.36–4.24 (m, 1H), 2.80 (s, 3H),1.81–1.48 (m, 3H), 1.04–0.85 (m, 6H).

EXAMPLE 13 (64)1-[(1R,2S)-2-(4-dimethylaminomethyl-3-fluorobenzoylamino)cyclohexyl]-N-[4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamideHydrochloride

TLC: Rf 0.35 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 8.03–7.88 (m, 1H), 7.68–7.54 (m, 2H), 7.59 and 7.41 (eachbrd, J=9.0 Hz, totally 1H), 6.55 and 6.32 (each brd, J=6.9 Hz, totally1H), 5.50–5.38 (m, 1H), 4.38–4.20 (m, 3H), 4.13–3.90 (m, 1H), 2.90–2.70(m, 7H), 2.10–1.40 (m, 17H), 1.04, 0.97, and 0.92 (each d, J=6.0 Hz,totally 6H).

EXAMPLE 13 (65)(2S)-N-[(2S)-4-methoxy-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-butyl]-4-methyl-2-benzyloxycarbonylaminopentanamide

TLC: Rf 0.36 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.40–7.20 (m, 6H), 5.41 (q, J=5.5 Hz, 1H), 5.17 (d, J=8.4Hz, 1H), 5.12 (s, 2H), 4.30–4.20 (m, 1H), 3.43 (t, J=5.1 Hz, 2H), 3.17(s, 3H), 2.78 (s, 3H), 2.40–2.20 (m, 2H) 1.80–1.45 (m, 3H), 0.95 (d,J=6.0 Hz, 6H).

EXAMPLE 13 (66)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[(2S)-4-methoxy-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-butyl]carboxamide

TLC: Rf 0.32 (n-hexane:ethyl acetate=1:2);

NMR (CDCl₃): δ 7.80–7.75 (m, 2H), 7.55 (d, J=8.1 Hz, 1H) 7.50–7.35 (m,3H), 7.22 (d, J=5.7 Hz, 1H), 5.42 (q, J=5.7 Hz, 1H), 4.35–4.25 (m, 1H),3.50–3.35 (m, 2H), 3.19 (s, 3H), 2.82 (q, J=4.8 Hz, 1H), 2.79 (s, 3H),2.40–2.20 (m, 2H), 2.05–1.40 (m, 8H).

EXAMPLE 13 (67)1-benzoylaminocyclohexyl-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.42 (n-hexane ethyl acetate=1:1);

NMR (CDCl₃): δ 8.02 (brd, J=6.6 Hz, 1H), 7.76 (d, J=7.8 Hz, 2H),7.58–7.43 (m, 3H), 6.07 (brs, 1H), 5.36 (ddd, J=10.2, 6.9, 4.2 Hz, 1H),2.76 (s, 3H), 2.37–2.20 (m, 2H), 2.06–1.90 (m, 2H), 1.90–1.30 (m, 9H),1.00 and 0.96 (each d, J=6.0 Hz, each 3H).

EXAMPLE 13 (68)1-[(1R,2S)-2-(4-dimethylaminomethyl-2-fluorobenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.42 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 8.09 (t, J=7.8 Hz, 1H), 7.71–7.42 (m, 3H), 6.28 (d, J=7.2Hz, 1H), 5.50–5.33 (m, 1H), 4.52–4.31 (m, 1H), 4.17 (brs, 2H), 4.13–3.95(m, 1H), 2.90–2.70 (m, 1H), 2.76 (brs, 6H), 2.15–1.38 (m, 11H), 1.54 (d,J=6.6 Hz, 6H), 0.94 and 0.89 (each d, J=6.3 Hz, each 3H).

EXAMPLE 13 (69)1-[1-morpholinocarbonylaminocyclohexyl]-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.48 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 8.17 (brd, J=6.6 Hz, 1H), 5.31 (ddd, J=9.9, 6.6, 3.9 Hz,1H), 4.43 (brs, 1H), 4.02 (septet, J=6.9 Hz, 1H), 3.72 (t, J=5.1 Hz,4H), 3.38 (t, J=5.1 Hz, 4H), 2.21–1.20 (m, 13H), 1.53 (d, J=6.9 Hz, 6H),1.00 and 0.97 (each d, J=5.7 Hz, each 3H).

EXAMPLE 13 (70)1-(1-morpholinocarbonylaminocyclohexyl)-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.55 (ethyl acetate);

NMR (CDCl₃): δ 8.17 (brd, J=6.3 Hz, 1H), 5.29 (m, 1H), 4.41 (brs, 1H),3.72 (t, J=4.5 Hz, 4H), 3.38 (t, J=4.5 Hz, 4H), 2.79 (s, 3H), 2.21–1.28(m, 13H), 1.00 and 0.97 (each d, J=5.7 Hz, each 3H).

EXAMPLE 13 (71)1-[1-t-butoxycarbonylaminocyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.69 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.49 (br, 1H), 5.38 (m, 1H), 4.70 (brs, 1H), 2.78 (s,3H), 2.11–1.20 (m, 22H), 1.01 and 0.97 (each d, J=6.0 Hz, each 3H).

EXAMPLE 13 (72)(2S)-N-[(2S)-4-methoxy-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-butyl]-4-methyl-2-benzyloxycarbonylaminopentanamide

TLC: Rf 0.49 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.40–7.25 (m, 5H), 7.24 (d, J=6.0 Hz, 1H), 5.42 (q, J=6.0Hz, 1H), 5.17 (d, J=7.8 Hz, 1H), 5.12 (s, 2H), 4.30–4.20 (m, 1H), 4.03(septet, J=6.9 Hz, 1H), 3.43 (t, J 5.0 Hz, 2H), 3.17 (s, 3H), 2.40–2.20(m, 2H), 1.80–1.40 (m, 3H), 1.53 (d, J=6.9 Hz, 6H), 0.95 (d, J=6.0 Hz,6H).

EXAMPLE 13 (73)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[(2S)-4-methoxy-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-butyl]carboxamide

TLC: Rf 0.37 (n-hexane:ethyl acetate=2:3);

NMR (CDCl₃) δ 7.80–7.75 (m, 2H), 7.57 (d, J=6.0 Hz, 1H) 7.50–7.35 (m,3H), 7.23 (d, J=6.0 Hz, 1H), 5.43 (q, J=6.0 Hz, 1H), 4.35–4.25 (m, 1H),4.04 (septet, J=6.9 Hz, 1H), 3.45–3.35 (m, 2H), 3.20 (s, 3H), 2.83 (q,J=4.7 Hz, 1H), 2.40–2.20 (m, 2H), 2.05–1.40 (m, 8H), 1.53 (d, J=6.9 Hz,6H).

EXAMPLE 13 (74)1-[(1R,2S)-2-(2-morpholinomethylbenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamideHydrochloride

TLC: Rf 0.66 (chloroform:methanol=19:1);

NMR (DMSO-d₆): δ 8.66 and 8.56 (each d, J=5.7 Hz, 1H), 8.45 and 8.31(each d, J=5.4 Hz, 1H), 7.75–7.69 (m, 1H), 7.60–7.48 (m, 3H), 5.06–4.98(m, 1H), 4.50–4.45 (m, 1H), 4.37–4.32 (m, 2H), 3.94–3.87 (m, 2H),3.78–3.65 (m, 2H), 3.41–3.00 (m, 4H), 2.82–2.71 (m, 4H), 2.00–1.22 (m,11H), 1.92–0.85, 0.83, and 0.79 (m, d, and d, J=6.3 Hz, totally 6H).

EXAMPLE 13 (75)1-[1-morpholinocarbonylaminocyclohexyl]-N-[(2S)-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-hexyl]carboxamide

TLC: Rf 0.38 (n-hexane:ethyl acetate=1:2);

NMR (CDCl₃): δ 8.16 (brd, J=6.6 Hz, 1H), 5.29 (ddd, J=9.0, 6.6, 5.1 Hz,1H), 4.43 (brs, 1H), 4.03 (septet, J=6.9 Hz, 1H), 3.72 (t, J=4.8 Hz,4H), 3.38 (t, J=4.8 Hz, 4H), 2.20–1.20 (m, 16H), 1.53 (d, J=6.9 Hz, 6H),0.89 (t, J=6.6 Hz, 3H).

EXAMPLE 13 (76)1-(1-benzoylaminocyclohexyl)-N-[(2S)-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-hexyl]carboxamide

TLC: Rf 0.32 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 8.02 (brd, J=6.9 Hz, 1H), 7.78 (d, J=6.9 Hz, 2H),7.59–7.44 (m, 3H), 6.09 (brs, 1H), 5.33 (ddd, J=9.0, 6.9, 5.1 Hz, 1H),4.00 (septet, J=6.6 Hz, 1H), 2.40–1.30 (m, 16H), 1.52 (d, J=6.6 Hz, 6H),0.87 (t, J=7.2 Hz, 3H).

EXAMPLE 13 (77)1-[1-(4-dimethylaminomethylbenzoylamino)cyclohexyl]-N-[4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.43 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 8.02 (d, J=6.9 Hz, 1H), 7.73 (d, J=8.3 Hz, 2H), 7.43 (d,J=8.3 Hz, 2H), 6.05 (s, 1H), 5.45–5.30 (m, 1H), 4.01 (septet, J=6.9 Hz,1H), 3.51 (s, 2H), 2.35–2.20 (m, 2H), 2.28 (s, 6H), 2.10–1.90 (m, 2H),1.85–1.30 (m, 9H), 1.52 (d, J=6.9 Hz, 6H), 1.01 (d, J=6.0 Hz, 3H), 0.97(d, J=6.0 Hz, 3H).

EXAMPLE 13 (78)1-[(1R,2S)-2-(3-morpholinomethylbenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamideHydrochloride

TLC: Rf 0.30 (n-hexane ethyl acetate=1:1);

NMR (DMSO-d₆): δ 8.68 and 8.57 (each d, J=5.4 Hz, totally 1H), 8.43 and8.30 (each d, J=8.1 Hz, totally 1H), 7.78–7.75 (m, 1H), 7.55–7.46 (m,3H), 5.07–4.99 (m, 1H), 4.50–4.24 (m, 3H), 4.00–3.66 (m, 5H), 3.41–3.00(m, 4H), 2.80–2.71 (m, 1H), 2.00–1.23 (m, 11H), 1.46 (d, J=6.6 Hz, 3H),1.43 (d, J=6.6 Hz, 3H), 0.90, 0.86, 0.85, and 0.82 (each d, J=6.6 Hz,totally 6H).

EXAMPLE 13 (79)1-[1-(3-dimethylaminomethylbenzoylamino)cyclohexyl]-N-[4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.53 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.97 (d, J=6.9 Hz, 1H), 7.76 (s, 1H), 7.69 (d, J=7.5 Hz,1H), 7.50 (d, J=7.5 Hz, 1H), 7.43 (t, J=7.5 Hz, 1H), 6.22 (brs, 1H),5.45–5.30 (m, 1H), 4.01 (septet, J=6.9 Hz, 1H), 3.52 (s, 2H), 2.40–2.15(m, 2H), 2.29 (s, 6H), 2.10–1.90 (m, 2H), 1.85–1.30 (m, 9H), 1.52 (d,J=6.9 Hz, 6H), 1.01 (d, J=6.0 Hz, 3H), 0.97 (d, J=6.0 Hz, 3H).

EXAMPLE 13 (80)1-[(1R,2S)-2-(2-pyrrolidin-1-ylmethylbenzoylamino)cyclohexyl]-N-[4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamidehydrochloride

TLC: Rf 0.46 and 0.35 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 8.65 and 8.55 (each d, J=6.6 Hz, totally 1H), 8.42 and8.28 (each d, J=8.4 Hz, totally 1H), 7.74–7.67 (m, 1H), 7.56–7.46 (m,3H), 5.05–4.97 (m, 1H), 4.46–4.22 (m, 3H), 3.26–3.00 (m, 4H), 2.81–2.67(m, 1H), 2.76 and 2.73 (each s, totally 3H), 2.13–1.22 (m, 15H), 0.88,0.87, 0.84, and 0.81 (each d, J=6.0 Hz, totally 6H).

EXAMPLE 13 (81)1-[(1R,2S)-2-(2-pyrrolidin-1-ylmethylbenzoylamino)cyclohexyl]-N-[4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamideHydrochloride

TLC: Rf 0.57 and 0.46 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 8.67 and 8.56 (each d, J=6.6 Hz, totally 1H), 8.41 and8.26 (each d, J=7.8 Hz, totally 1H), 7.74–7.70 (m, 1H), 7.60–7.45 (m,3H), 5.05–4.96 (m, 1H), 4.46–4.23 (m, 3H), 4.00–3.86 (m, 1H), 3.21–3.01(m, 4H), 2.80–2.70 (m, 1H), 2.07–1.01 (m, 21H), 0.89, 0.88, 0.85, and0.81 (each d, J=6.6 Hz, totally 6H).

EXAMPLE 13 (82)1-(1-benzoylaminocyclohexyl)-N-[1-(5-(2-dimethylaminoethylthio)-1,3,4-oxadiazol-2-yl)-4-methyl-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.21 (chloroform:methanol:water=9:1:0.1);

NMR (CDCl₃): δ 8.01 (brd, J=6.9 Hz, 1H), 7.82–7.74 (m, 2H), 7.60–7.40(m, 3H), 6.07 (brs, 1H), 5.42–5.31 (m, 1H), 3.52–3.40 (m, 2H), 2.78 (t,J=6.9 Hz, 2H), 2.34 (s, 6H), 2.05–1.30 (m, 13H), 1.01 and 0.97 (each d,J=6.0 Hz, each 3H).

EXAMPLE 13 (83)1-[1-(4-dimethylaminomethylbenzoylamino)cyclohexyl]-N-[1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-hexyl]carboxamide

TLC: Rf 0.55 (chloroform methanol:acetic acid=10:2:1);

NMR (CDCl₃): δ 8.02 (brd, J=6.9 Hz, 1H), 7.74 (d, J=8.4 Hz, 2H), 7.43(d, J=8.4 Hz, 2H), 6.09 (brs, 1H), 5.31 (m, 1H), 4.01 (m, 1H), 3.54(brs, 2H), 2.60–1.20 (m, 28H), 0.87 (t, J=7.2 Hz, 3H).

EXAMPLE 13 (84)1-(1-acetylaminocyclohexyl)-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.61 (chloroform:methanol=9:1);

NMR (CDCl₃) δ 7.91 (brd, J=6.9 Hz, 1H), 5.40 (brs, 1H), 5.31 (m, 1H),4.02 (septet, J=6.9 Hz, 1H), 2.20–1.25 (m, 13H), 2.08 (s, 3H), 1.53 (d,J=6.6 Hz, 6H), 1.01 (d, J=6.0 Hz, 3H), 0.98 (d, J=6.6 Hz, 3H).

EXAMPLE 13 (85)1-[1-(pyridin-3-ylcarbonylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.47 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 9.01 (brs, 1H), 8.77 (brs, 1H), 8.12 (d, J=8.1 Hz, 1H),7.79 (d, J=6.9 Hz, 1H), 7.48–7.38 (m, 1H), 6.20 (brs, 1H), 5.43–5.32 (m,1H), 4.08–3.95 (m, 1H), 2.37–1.28 (m, 13H), 1.52 (d, J=6.9 Hz, 6H), 1.02and 0.98 (each d, J=6.0 Hz, totally 6H).

EXAMPLE 13 (86)1-[1-(pyridin-4-ylcarbonylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.46 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 8.78 (brd, J=5.7 Hz, 2H), 7.71 (d, J=7.2 Hz, 1H), 7.62(d, J=5.7 Hz, 2H), 6.17 (brs, 1H), 5.43–5.33 (m, 1H), 4.08–3.93 (m, 1H),2.35–1.30 (m, 13H), 1.52 (d, J=6.9 Hz, 6H), 1.02 and 0.98 (each d, J=6.0Hz, totally 6H).

EXAMPLE 13 (87)1-[1-(2-dimethylaminomethylbenzoylamino)cyclohexyl]-N-[4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.66 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 10.7 (brs, 1H), 8.50 (brd, J=6.6 Hz, 1H), 7.87 (m, 1H),7.45–7.36 (m, 2H), 7.19 (m, 1H), 5.37 (m, 1H), 4.01 (septet, J=6.9 Hz,1H), 3.84 (brd, J=12 Hz, 1H), 3.32 (brd, J=12 Hz, 1H), 2.57 (m, 1H),2.30–1.25 (m, 12H), 2.23 (s, 6H), 1.52 (d, J=6.6 Hz, 3H), 1.51 (d, J=6.6Hz, 3H), 1.02 (d, J=6.0 Hz, 3H), 0.97 (d, J=6.3 Hz, 3H).

EXAMPLE 13 (88)1-[1-(4-morpholinomethylbenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.66 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 8.03 (brd, J=6.6 Hz, 1H), 7.73 (d, J=8.4 Hz, 2H), 7.44(d, J=8.4 Hz, 2H), 6.05 (brs, 1H), 5.37 (m, 1H), 4.01 (septet, J=6.6 Hz,1H), 3.72 (brt, J=4.5 Hz, 4H), 3.56 (s, 2H), 2.46 (brt, J=4.5 Hz, 4H),2.27 (m, 2H), 1.98 (m, 2H), 1.85–1.30 (m, 9H), 1.52 (d, J=6.6 Hz, 6H),1.01 (d, J=6.0 Hz, 3H), 0.97 (d, J=6.3 Hz, 3H).

EXAMPLE 13 (89)1-(4-benzoylamino-1-t-butoxycarbonylpiperidin-4-yl)-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.71 (n-hexane:ethyl acetate=1:2);

NMR (CDCl₃): δ 8.06 (br, 1H), 7.76 (d, J=6.9 Hz, 2H), 7.60–7.42 (m, 3H),6.13 (brs, 1H), 5.37 (ddd, J=9.9, 6.6, 3.6 Hz, 1H), 4.00 (septet, J=6.6Hz, 1H), 3.90–3.70 (m, 2H), 3.35–3.20 (m, 2H), 2.40–2.10 (m, 4H),1.90–1.40 (m, 18H), 1.01 and 0.97 (each d, J=6.3 Hz, each 3H).

EXAMPLE 13 (90)1-(1-benzoylaminocyclopentyl)-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.60 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.89 (brd, J=6.9 Hz, 1H), 7.75 (m, 2H), 7.54 (m, 1H),7.46 (m, 2H), 6.37 (brs, 1H), 5.38 (m, 1H), 4.00 (septet, J=6.9 Hz, 1H),2.43 (m, 2H), 2.12 (m, 2H), 1.88–1.58 (m, 7H), 1.52 (d, J=6.9 Hz, 6H),1.01 (d, J=6.3 Hz, 3H), 0.96 (d, J=6.3 Hz, 3H).

EXAMPLE 13 (91)1-[1-(4-dimethylaminomethylbenzoylamino)cyclopentyl]-N-[4-methyl-1-(5-(1-methylethylthio)-1-oxo-1,3,4-oxadiazol-2-yl)-2-pentyl]carboxamide

TLC: Rf 0.40 (chloroform methanol=9:1);

NMR (CDCl₃): δ 7.90 (brd, J=6.6 Hz, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.41(d, J=8.4 Hz, 2H), 6.36 (brs, 1H), 5.38 (m, 1H), 4.01 (septet, J=6.9 Hz,1H), 3.50 (s, 2H), 2.43 (m, 2H), 2.26 (s, 6H), 2.12 (m, 2H), 1.88–1.60(m, 7H), 1.52 (d, J=6.9 Hz, 6H), 1.01 (d, J=6.0 Hz, 3H), 0.96 (d, J=6.3Hz, 3H).

EXAMPLE 13 (92)1-[1-(4-morpholinomethylbenzoylamino)cyclopentyl]-N-[4-methyl-1-(5-(i-methylethylthio)-1-oxo-1,3,4-oxadiazol-2-yl)-2-pentyl]carboxamide

TLC: Rf 0.65 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.89 (brd, J=6.9 Hz, 1H), 7.70 (d, J=8.4 Hz, 2H), 7.43(d, J=8.4 Hz, 2H), 6.34 (brs, 1H), 5.38 (m, 1H), 4.01 (septet, J=6.9 Hz,1H), 3.72 (brt, J=4.5 Hz, 4H), 3.55 (s, 2H), 2.45 (brt, J=4.5 Hz, 4H),2.43 (m, 2H), 2.11 (m, 2H), 1.88–1.60 (m, 7H), 1.52 (d, J=6.9 Hz, 6H),1.01 (d, J=6.0 Hz, 3H), 0.96 (d, J=6.3 Hz, 3H).

EXAMPLE 13 (93)1-(4-benzoylamino-1-methoxycarbonylpiperidin-4-yl)-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1-oxo-1,3,4-oxadiazol-2-yl)-2-pentyl]carboxamide

TLC: Rf 0.50 (chloroform methanol 9:1);

NMR (CDCl₃): δ 8.06 (br, 1H), 7.75 (d, J=6.9 Hz, 1H), 7.61–7.42 (m, 3H),6.10 (brs, 1H), 5.38 (ddd, J=9.9, 6.6, 3.6 Hz, 1H), 4.05 (septet, J=6.6Hz, 1H), 3.90–3.70 (m, 2H), 3.35–3.20 (m, 2H), 3.70 (s, 3H), 3.43–3.31(m, 2H), 2.40–2.11 (m, 4H), 1.90–1.50 (m, 9H), 1.01 and 0.97 (each d,J=6.0 Hz, each 3H).

EXAMPLE 13 (94)1-[1-(pyridin-2-ylcarbonylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.62 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 8.62–8.57 (m, 1H), 8.31 (brs, 1H), 8.18 (d, J=7.8 Hz,1H), 7.95 (brd, J=6.6 Hz, 1H), 7.88 (dt, J=1.5, 7.8 Hz, 1H), 7.48 (ddd,J=7.8, 4.5, 1.5 Hz, 1H), 5.41–5.32 (m, 1H), 4.08–3.92 (m, 1H), 2.40–1.23(m, 13H), 1.52 (d, J=6.9 Hz, 6H), 0.99 and 0.94 (each d, J=6.0 Hz, each3H).

EXAMPLE 13 (95)1-[1-(4-(N-t-butoxycarbonyl)piperazin-1-ylcarbonylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.38 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 8.16 (brd, J=6.3 Hz, 1H), 5.30 (ddd, J=9.9, 6.6, 4.2 Hz,1H), 4.42 (brs, 1H), 4.01 (septet, J=6.6 Hz, 1H), 3.51–3.38 (m, 8H),2.21–1.30 (m, 28H), 0.98 and 0.96 (each d, J=6.3 Hz, each 3H).

EXAMPLE 13 (96)1-[1-(t-butoxycarbonylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.75 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): 7.43 (br, 1H), 5.39 (ddd, J=10.5, 7.2, 3.0 Hz, 1H), 4.69(brs, 1H), 4.03 (septet, J=6.6 Hz, 1H), 2.11–1.21 (m, 28H), 1.02 and0.95 (each d, J=6.0 Hz, each 3H).

EXAMPLE 13 (97)1-cyclohexyl-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.35 (n-hexane ethyl acetate=3:1);

NMR (CDCl₃): δ 6.02 (d, J=8.0 Hz, 1H), 5.43 (ddd, J=10.1, 8.0 and 3.9Hz, 1H), 4.13–3.96 (m, 1H), 2.24–2.10 (m, 1H), 1.94–1.15 (m, 13H), 1.54(d, J=6.9 Hz, 6H), 1.03 and 0.97 (each d, J=6.3 Hz, each 3H).

EXAMPLE 13 (98)1-(1-(2-butynoylamino)cyclohexyl)-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.41 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 9.00 (d, J=1.8 Hz, 1H), 8.77 (dd, J=4.8, 1.8 Hz, 1H),8.12 (dt, J=7.8, 1.8 Hz, 1H), 7.70 (d, J=7.2 Hz, 1H), 7.43 (dd, J=7.8,4.8 Hz, 1H), 6.16 (s, 1H), 5.41–5.34 (m, 1H,), 4.06–3.97 (m, 1H),2.34–2.19 (m, 2H), 2.08–1.98 (m, 2H), 1.81–1.26 (m, 9H), 1.51 (d, J=6.6Hz, 6H), 1.01 (d, J=6.0 Hz, 3H), 0.98 (d, J=6.0 Hz, 3H).

EXAMPLE 13 (99)1-(1-cyclohexyl)-N-[4-methyl-1-(2-(2-dimethylethylthio)-1,3,4-oxadiazol-5-yl)-1-oxo-2-pentyl]carboxamideHydrochloride

TLC: Rf 0.54 (chloroform:methanol:ammonia water=190:10:1);

NMR (CDCl₃): δ 13.08 (brs, 1H), 5.98 (d, J=6.9 Hz, 1H), 5.47–5.37 (m,1H), 3.97–3.84 (m, 2H), 3.62–3.44 (m, 2H), 2.93 (brs, 6H), 2.24–2.11 (m,1H), 2.02–1.11 (m, 13H), 1.03 and 0.99 (each d, J=6.0 Hz, each 3H).

EXAMPLE 13 (100)1-[(1R,2S)-2-(2-butynoylamino)cyclohexyl]-N-[4-methyl-1-(2-(1-methylethylthio)-1,3,4-oxadiazol-5-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.35 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 6.82 and 6.67 (each brd, J=9.0 Hz, 1H), 6.27 and 6.17(each brd, J=7.5 Hz, 1H), 5.45 and 5.41 (each m, 1H), 4.20–4.08 (m, 1H),4.06 and 4.05 (each septet, J=6.9 Hz, 1H), 2.77 and 2.74 (each m, 1H),2.00–1.35 (m, 11H), 1.93 and 1.92 (each s, 3H), 1.55 and 1.54 (each d,J=6.9 Hz, 6H), 1.04 (d, J=6.3 Hz, 3H), 0.99 and 0.98 (each d, J=6.6 Hz,3H).

EXAMPLE 13 (101)1-(4-benzoylamino-1,1-dimethylpiperidinium-4-yl)-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1-oxo-1,3,4-oxadiazol-2-yl)-2-pentyl]carboxamideIodide

TLC: Rf 0.22 (chloroform:methanol:acetic acid=10:2:1);

NMR (CDCl₃): δ 8.98 (brs, 1H), 8.17 (d, J=7.2 Hz, 2H), 7.88 (d, J=7.2Hz, 1H), 7.50–7.35 (m, 3H), 5.31–5.25 (m, 1H), 4.10–3.10 (m, 11H),2.90–2.50 (m, 4H), 2.20–1.20 (m, 9H), 0.93 and 0.82 (each d, J=5.7 Hz,each 3H).

EXAMPLE 13 (102)1-[(1R,2S)-2-(4-(2-dimethylaminoethyl)benzoylamino)cyclohexyl]-N-[4-methyl-1-(2-(1-methylethylthio)-1,3,4-oxadiazol-5-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.38 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.72 and 7.68 (each d, J=8.1 Hz, 2H), 7.26 and 7.24 (eachd, J=8.1 Hz, 2H), 7.21 and 7.15 (each brd, J=9.0 Hz, 1H), 6.33 and 6.27(each brd, J=7.5 Hz, 1H), 5.43 and 5.38 (each m, 1H), 4.38–4.25 (m, 1H),4.05 and 4.03 (each septet, J=6.9 Hz, 1H), 2.88–2.77 (m, 3H), 2.58–2.50(m, 2H), 2.30 (s, 6H), 2.10–1.40 (m, 11H), 1.54 and 1.53 (each d, J=6.9Hz, 6H), 1.02 and 0.94 (each d, J=6.0 Hz, 3H), 0.91 and 0.85 (each d,J=6.3 Hz, 3H).

EXAMPLE 13 (103)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[(2S)-4-methyl-1-(2-(2-morpholinoethylthio)-1,3,4-oxadiazol-5-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.49 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.77–7.75 (m, 2H), 7.49–7.40 (m, 3H), 7.19 (d, J=8.1 Hz,1H), 6.36 and 6.27 (each d, J=7.5 Hz, total 1H), 5.47–5.41 (m, 1H),4.38–4.28 (m, 1H), 3.70 (t, J=4.5 Hz, 4H), 3.51 (t, J=6.9 Hz, 2H),2.87–2.78 (m, 3H), 2.53 (t, J=4.5 Hz, 4H), 2.13–1.41 (m, 1H), 1.01,0.95, 0.91, and 0.85 (each d, J=6.3 Hz, total 6H).

EXAMPLE 13 (104)1-[1-(4-(2-dimethylaminoethyl)benzoylamino)cyclohexyl]-N-[4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf0.31 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 8.05 (brd, J=6.9 Hz, 1H), 7.70 (d, J=8.1 Hz, 2H), 7.31(d, J=8.1 Hz, 2H), 6.03 (brs, 1H), 5.37 (m, 1H), 4.01 (septet, J=6.9 Hz,1H), 2.85 (t, J=8.0 Hz, 2H), 2.56 (t, J=8.0 Hz, 2H), 2.30 (s, 6H), 2.25(m, 2H), 1.98 (m, 2H), 1.85–1.30 (m, 9H), 1.52 (d, J=6.6 Hz, 6H), 1.01(d, J=5.7 Hz, 3H), 0.97 (d, J=6.0 Hz, 3H).

EXAMPLE 13 (105)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[4-methyl-1-(2-(2-pyrrolidinoethylthio)-1,3,4-oxadiazol-5-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.59 (chloroform:methanol:water=40:10:1);

NMR (CDCl₃): δ 7.80–7.75 (m, 2H), 7.52–7.39 (m, 3H), 7.26 and 7.20 (eachd, J=8.4 Hz, total 1H), 6.30 and 6.25 (each d, J 8.1 Hz, total 1H),5.47–5.34 (m, 1H), 4.36–4.29 (m, 1H), 3.53–3.47 (m, 2H), 2.95–2.91 (m,2H), 2.88–2.84 (m, 1H), 2.61 (br-s, 4H), 2.08–1.46 (m, 15H), 1.01, 0.97,0.93, and 0.85 (each d, J=6.6 Hz, total 6H).

EXAMPLE 13 (106)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[(2S)-1-(2-cyclohexylthio-1,3,4-oxadiazol-5-yl)-4-methyl-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.28 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 7.82–7.74 (m, 2H), 7.53–7.38 (m, 3H), 7.20 (brd, J=8.4Hz, 1H), 6.35–6.22 (m, 1H), 5.50–5.40 (m, 1H), 4.38–4.26 (m, 1H),3.95–3.84 (m, 1H), 2.91–2.83 (m, 1H), 2.27–1.25 (m, 21H), 0.91 and 0.85(each d, J=6.3 Hz, each 3H).

EXAMPLE 13 (107)1-cyclohexyl-N-[(2S)-1-(2-cyclohexylthio-1,3,4-oxadiazol-5-yl)-4-methyl-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.70 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 6.03 (brd, J=7.8 Hz, 1H), 5.48–5.38 (m, 1H), 3.95–3.83(m, 1H), 2.27–2.11 and 1.93–1.17 (each m, total 24H), 1.02 and 0.97(each d, J=6.3 Hz, each 3H).

EXAMPLE 13 (108)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[1-(2-(3-dimethylaminopropylthio)-1,3,4-oxadiazol-5-yl)-4-methyl-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.55 (chloroform:methanol=4:1);

NMR (CDCl₃): δ 7.83–7.75 (m, 2H), 7.53–7.39 (m, 3H), 7.30–7.20 (m, 1H),6.27 and 6.23 (each brd, J=6.6 Hz, totally 1H) 5.50–5.38 (m, 1H),4.40–4.30 (m, 1H), 3.43–3.33 (m, 2H), 2.89 (m, 1H), 2.42 (t, J=6.9 Hz,2H), 2.24 (s, 6H), 2.10–1.40 (m, 13H), 1.01, 0.94, 0.90 and 0.84 (eachd, J=6.3 Hz, totally 6H).

EXAMPLE 13 (109)1-cyclohexyl-N-[4-methyl-1-(2-(3-dimethylaminopropylthio)-1,3,4-oxadiazol-5-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.42 (chloroform:methanol=4:1);

NMR (CDCl₃): δ 6.04 (brd, J=7.5 Hz, 1H), 5.42 (ddd, J=9.9, 7.8, 3.9 Hz,1H), 3.37 (dt, J=1.2, 6.9 Hz, 2H), 2.41 (t, J=6.9 Hz, 2H), 2.23 (s, 6H),2.22–1.19 (m, 14H), 1.02 and 0.97 (each d, J=6.3 Hz, each 3H).

EXAMPLE 13 (110)1-[(1R,2S)-2-(4-(dimethylamino)but-2-ynoylamino)cyclohexyl]-N-[4-methyl-1-(2-(1-methylethylthio)-1,3,4-oxadiazol-5-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.54 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 6.90 and 6.80 (each brd, J=9.0 Hz, 1H), 6.24 and 6.19(each brd, J=7.2 Hz, 1H), 5.45 and 5.42 (each m, 1H), 4.20–4.10 (m, 1H),4.05 (septet, J=6.9 Hz, 1H), 3.37 (s, 2H), 2.82–2.75 (m, 1H), 2.32 and2.31 (each s, 6H), 2.00–1.35 (m, 11H), 1.55 (d, J=6.6 Hz, 6H), 1.05 and1.04 (each d, J=6.0 Hz, 3H), 0.99 and 0.98 (each d, J=6.3 Hz, 3H).

EXAMPLE 13 (111)1-[1-(4-(dimethylamino)but-2-ynoylaminocyclohexyl)]-N-[4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.51 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.48 (brd, J=6.9 Hz, 1H), 5.81 (brs, 1H), 5.35 (m, 1H),4.03 (septet, J=6.9 Hz, 1H), 3.40 (s, 2H), 2.36 (s, 6H), 2.12 (m, 2H),1.92 (m, 2H), 1.85–1.30 (m, 9H), 1.53 (d, J=6.6 Hz, 6H), 1.01 (d, J=6.0Hz, 3H), 0.97 (d, J=6.3 Hz, 3H).

EXAMPLE 13 (112)1-[(1R,2S)-2-dimethylaminocyclohexyl]-N-[(2S)-4-methyl-1-(2-(1-methylethylthio)-1,3,4-oxadiazol-5-yl)-1-oxo-2-pentyl]carboxamideHydrochloride

TLC: Rf 0.47 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 9.24–8.87 (m, 2H), 5.13–4.99 (m, 1H), 4.08–3.88 (m,1H), 3.30–3.00 (m, 2H), 2.85–2.53 (m, 6H), 2.29–2.10 and 2.05–1.01 (eachm, total 11H), 1.47 (d, J=6.9 Hz, 6H), 0.93 (d, J=6.0 Hz, 6H).

EXAMPLE 13 (113)1-cyclohexyl-N-[4-methyl-1-(2-(2-morpholinoethylthio)-1,3,4-oxadiazol-5-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.57 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 6.00 (d, J=8.1 Hz, 1H), 5.45–5.38 (m, 1H), 3.71 (t, J=4.5Hz, 4H), 3.51 and 3.50 (each t, J=6.6 Hz, total 2H), 2.81 (t, J=6.6 Hz,2H), 2.54 (t, J=4.5 Hz, 4H), 2.20–2.13 (m, 1H) 1.89–1.23 (m, 13H), 1.03(d, J=6.3 Hz, 3H), 0.97 (d, J=6.3 Hz, 3H).

EXAMPLE 13 (114)1-cyclohexyl-N-[4-methyl-1-oxo-1-(2-(2-pyrrolidinoethylthio)-1,3,4-oxadiazol-5-yl)-2-pentyl]carboxamide

TLC: Rf 0.53 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 6.02 (d, J=7.8 Hz, 1H), 5.46–5.39 (m, 1H), 3.51 and 3.50(each t, J=6.6 Hz, total 2H), 2.93 (t, J=6.6 Hz, 2H), 2.61 (br-s, 4H),2.20–2.11 (m, 1H), 1.89–1.12 (m, 17H), 1.03 (d, J=6.3 Hz, 3H), 0.97 (d,J=6.3 Hz, 3H).

EXAMPLE 13 (115)1-(1-benzoylaminocyclohexyl)-N-[4-methyl-1-(2-(3-dimethylaminopropylthio)-1,3,4-oxadiazol-5-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.50 (chloroform:methanol:water=4:1:0.1);

NMR (CDCl₃): δ 8.02 (brd, J=6.6 Hz, 1H), 7.78 (d, J=8.1 Hz, 2H),7.58–7.40 (m, 3H), 6.08 (brs, 1H), 5.36.(ddd, J=10.2, 6.6, 3.9 Hz, 1H),3.36 (m, 2H), 2.49 (t, J=6.9 Hz, 2H), 2.29 (s, 6H), 2.20–1.30 (m, 15H),1.01 and 0.97 (each d, J=6.0 Hz, each 3H).

EXAMPLE 13 (116)1-cyclohexyl-N-[(2S)-4-methyl-1-(2-benzylthio-1,3,4-oxadiazol-5-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.71 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.48–7.40 (m, 2H), 7.40–7.26 (m, 3H), 6.01 (brd, J=7.5Hz, 1H), 5.46–5.36 (m, 1H), 4.56 (d, J=13.2 Hz, 1H), 4.54 (d, J=13.2 Hz,1H), 2.23–2.08 (m, 1H), 1.93–1.12 (m, 13H), 1.03 and 0.97 (each d, J=6.3Hz, each 3H).

EXAMPLE 13 (117)1-(1-benzoylaminocyclohexyl)-N-[(2S)-1-(2-cyclohexylthio-1,3,4-oxadiazol-5-yl)-4-methyl-1-oxo-2-pentyl]carboxamide

TLC: Rf0.66 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 8.01 (brd, J=6.9 Hz, 1H), 7.81–7.74 (m, 2H), 7.60–7.43(m, 3H), 6.07 (brs, 1H), 5.43–5.33 (m, 1H), 3.91–3.78 (m, 1H), 2.37–1.25(m, 23H), 1.01 and 0.97 (each d, J=6.3 Hz, each 3H).

EXAMPLE 13 (118)1-(1-benzoylaminocyclohexyl)-N-[(2S)-1-(2-benzylthio-1,3,4-oxadiazol-5-yl)-4-methyl-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.56 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 8.03 (brd, J=6.6 Hz, 1H), 7.81–7.74 (m, 2H), 7.61–7.26(m, 8H), 6.08 (brs, 1H), 5.40–5.31 (m, 1H), 4.53 (d, J=12.9 Hz, 1H),4.51 (d, J=12.9 Hz, 1H), 2.35–1.28 (m, 13H), 1.01 and 0.97 (each d,J=6.0 Hz, each 3H).

EXAMPLE 13 (119)1-[(1R,2S)-2-(t-butoxycarbonylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(2-(1-methylethylthio)-1,3,4-oxadiazol-5-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.45 (n-hexane:ethyl acetate=2:1);

NMR (DMSO-d₆): δ 8.37 (d, J=6.0 Hz, 1H), 6.25 (d, J=8.4 Hz, 1H),5.11–5.00 (m, 1H), 4.06–3.74 (m, 2H), 2.64–2.51 (m, 1H), 1.87–1.11 (m,11H), 1.48 (d, J=6.6 Hz, 6H), 1.37 (s, 9H), 0.91 (d, J=6.3 Hz, 6H).

EXAMPLE 13 (120)1-(1-benzoylaminocyclohexyl)-N-[4-methyl-1-(2-(2-morpholinoethylthio)-1,3,4-oxadiazol-5-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.72 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 8.03 (d, J=6.6 Hz, 1H), 7.77 (d, J=7.8 Hz, 2H), 7.58–7.45(m, 3H), 6.06 (s, 1H), 5.39–5.30 (m, 1H), 3.69 (t, J=4.5 Hz, 4H), 3.48and 3.47 (each t, J=6.6 Hz, total 2H), 2.79 (t, J=6.6 Hz, 2H), 2.52 (t,J=4.5 Hz, 4H), 2.32–2.23 (m, 2H), 2.03–1.95 (m, 2H), 1.85–1.25 (m, 9H),1.01 (d, J=6.0 Hz, 3H), 0.97 (d, J=6.0 Hz, 3H).

EXAMPLE 13 (121)1-[(1R,2S)-2-(4-morpholinobut-2-ynoylamino)cyclohexyl]-N-[4-methyl-1-(2-(1-methylethylthio)-1,3,4-oxadiazol-5-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.53 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 6.91 and 6.83 (each brd, J=9.0 Hz, 1H), 6.19 and 6.16(each brd, J=7.5 Hz, 1H), 5.44 and 5.43 (each m, 1H), 4.20–4.08 (m, 1H),4.06 and 4.05 (each septet, J=6.9 Hz, 1H), 3.75–3.70 (m, 4H), 3.38 (s,2H), 2.80–2.73 (m, 1H), 2.57 (t, J=4.5 Hz, 4H), 2.00–1.35 (m, 11H), 1.55and 1.54 (each d, J=6.6 Hz, 6H), 1.05 and 1.04 (each d, J=6.3 Hz, 3H),0.99 and 0.98 (each d, J=6.3 Hz, 3H).

EXAMPLE 14 TO EXAMPLE 14(3)

By the same procedure as described in Reference Example 10, using thecompound prepared in Example 13 (71), 13(89), 13(96) or 13 (119) inplace of the compound prepared in Reference Example 9, the compounds ofthe present invention having the following physical data ware obtained.

EXAMPLE 141-(1-aminocyclohexyl)-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamidehydrochloride

TLC: Rf 0.58 (n-hexane:ethyl acetate=1:2);

NMR (CDCl₃): δ 8.79 (br, 3H), 7.90 (br, 1H), 5.42–5.30 (m, 1H), 2.78 (s,3H), 2.30–1.40 (m, 13H), 1.12–0.90 (m, 6H).

EXAMPLE 14 (1)1-(4-benzoylaminopiperidin-4-yl)-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamideHydrochloride

TLC: Rf 0.46 (chloroform:methanol:acetic acid=10:2:1);

NMR (DMSO-d₆): δ 8.72 (br, 1H), 8.37 (d, J=6.9 Hz, 1H), 8.30 (brs, 1H),7.89 (d, J=8.4 Hz, 2H), 7.60–7.43 (m, 3H), 5.01 (m, 1H), 3.95 (septet,J=6.9 Hz, 1H), 3.40–3.05 (m, 4H), 2.75–2.01 (m, 4H), 1.70–1.31 (m, 3H),1.46 (d, J=6.9 Hz, 6H) 0.84 and 0.81 (each d, J=5.4 Hz, each 3H).

EXAMPLE 14 (2)1-(1-aminocyclohexyl)-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamideHydrochloride

TLC: Rf 0.28 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 8.80 (brs, 3H), 7.87 (brd, J=6.0 Hz, 1H), 5.39 (m, 1H),4.02 (septet, J=6.6 Hz, 1H), 2.28–1.40 (m, 19H), 1.03–0.92 (m, 6H).

EXAMPLE 14 (3)1-[(1R,2S)-2-aminocyclohexyl]-N-[(2S)-4-methyl-1-(2-(1-methylethylthio)-1,3,4-oxadiazol-5-yl)-1-oxo-2-pentyl]carboxamideHydrochloride

TLC: Rf 0.49 (chloroform:methanol:acetic acid=10:1:1);

NMR (DMSO-d₆): δ 8.81 (d, J=5.4 Hz, 1H), 8.17–7.48 (br, 3H), 5.15–5.02(m, 1H), 4.04–3.89 (m, 1H), 3.40–3.21 (m, 1H), 2.85–2.73 (m, 1H),1.97–1.20 (m, 11H), 1.47 (d, J=6.6 Hz, 6H), 0.93 (d, J=6.3 Hz, 6H).

EXAMPLE 151-[(1R,2S)-2-benzylaminocyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamidehydrochloride

By the same procedure as described in Reference Example 15→Example3→Reference Example 18 using(2S)-2-amino-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)pentanolhydrochloride in place of the compound prepared in Reference Example 14and 2-N-benzyl-N-t-butoxycarbonylaminocyclohexanecarboxylic acid inplace of the N-benzyloxycarbonyl-(L)-leucine, the compound of thepresent invention having the following physical data was obtained.

TLC: Rf 0.31 (ethyl acetate);

NMR (DMSO-d₆): δ 9.10–8.60 (m, 3H), 7.62–7.30 (m, 5H), 5.18–5.04 (m,1H), 4.30–3.97 (m, 2H), 3.31–3.10 and 3.10–2.93 (each br, each 1H), 2.78(s, 3H), 2.21–1.16 (m, 11H), 0.95 and 0.94 (each d, J=6.2 Hz, each 3H).

REFERENCE EXAMPLE 24(3S)-3-(t-butoxycarbonylamino)-5-methylhexanenitrile

To a solution of the compound prepared in Reference Example 3 (2.04 g)in N,N-dimethylformamide (15 ml) were added imidazole (1.26 g) andt-butyldimethylsilylchloride (2.79 g) and the mixture was stirred for 3hours at room temperature. To the reaction mixture was added water andwas extracted with ethyl acetate. The organic layer was washed withwater, saturated aqueous solution of sodium chloride and dried andconcentrated. The residue was purified by column chromatography onsilica gel (n-hexane:ethyl acetate=19:1) to give the title compound(3.06 g) having the following physical data.

TLC: Rf 0.51, 0.47 (hexane:ethyl acetate=5:1).

NMR (CDCl₃): δ 4.64–4.40 (m, 2H), 3.82 (m, 1H), 1.80–1.40 (m, 12H),1.05–0.84 (m, 15H), 0.25–0.10 (m, 6H).

REFERENCE EXAMPLE 253-(t-butoxycarbonylamino)-2-(t-butyldimethylsilyloxy)-5-methyl-N′-hydroxyhexanimidamide

To a solution of the compound prepared in Reference Example 24 (4.27 g)in methanol (36 ml) were added hydroxylamine hydrochloride (2.50 g) andtriethylamine (5.02 ml) at room temperature and the mixture was stirredat 50° C. The reaction mixture was concentrated and to the residue wereadded water and ethyl acetate. The organic layer was washed withsaturated aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate and was concentrated. The residue was purified bycolumn chromatography on silica gel (chloroform:methanol=20:1) to givethe title compound (4.44 g) having the following physical data.

TLC: Rf 0.44 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 6.60–6.00 and 4.86–4.42 (each m, totally 3H), 4.08–4.00(m, 1H), 3.90–3.70 (m, 1H), 1.44 (s, 9H), 1.42–1.15 (m, 3H), 1.00–0.85(m, 15H), 0.16–0.08 (m, 6H).

REFERENCE EXAMPLE 26(2S)-2-(t-butoxycarbonylamino)-4-methyl-1-(5-thioxo-1,2,4-oxadiazolin)-1-(t-butyldimethylsilyloxy)-2-pentylamide

To a solution of the compound prepared in Reference Example 25 (4.43 g)in acetonitrile (114 ml) was added DBU (1,8-diazabicyclo[4.3.0]non-5-one(6.81 ml) and further was added thiocarbonyldiimidazole (TCDI) (2.23 g)at 0° C. and the mixture was stirred for 13 hours at room temperature.The reaction mixture was poured into 1N hydrochloric chloride (100 ml)and the mixture was extracted with ethyl acetate and was concentrated.The residue was diluted by 1N aqueous solution of sodium hydroxide,washed with diethyl ether and the solution was adjusted to pH 2 byadding 1N hydrochloric acid. The solution was extracted with ethylacetate and the organic layer was washed with saturated aqueous solutionof sodium chloride and dried over anhydrous magnesium sulfate and wasconcentrated. The residue was purified by column chromatography onsilica gel (n-hexane:ethyl acetate=4:1) to give the title compound (4.22g) having the following physical data.

TLC: Rf 0.44 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 6.73–5.70 (m, 1H), 4.82–3.75 (m, 2H), 1.83–1.15 (m, 3H),1.43 and 1.39 (each s, totally 9H), 1.01–0.82 (m, 15H), 0.23–0.02 (m,6H).

REFERENCE EXAMPLE 27(2S)-4-methyl-1-(5-thioxo-1,2,4-oxadiazolin-3-yl)-1-(t-butyldimethylsilyloxy)-2-pentylamineHydrochloride

By the same procedure as described in Reference Example 10 using thecompound prepared in Reference Example 26 (2.155 g) in place of thecompound prepared in Reference Example 9, the title compound (1.234 g)having the following physical data was obtained.

TLC: Rf 0.41 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 8.30–8.00 (br, 3H), 5.06–4.87 (m, 1H), 3.47–3.34 (m,1H), 1.88–1.32 (m, 3H), 0.96–0.78 (m, 15H), 0.11 and 0.03 (each s,totally 6H).

REFERENCE EXAMPLE 28(2S)-N-[(2S)-4-methyl-1-(5-thioxo-1,2,4-oxadiazolin-3-yl)-1-(t-butyldimethylsilyloxy)-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

By the same procedure as described in Reference Example 11 using thecompound prepared in Reference Example 27 (1.10 g) in place of thecompound prepared in Reference Example 10, the title compound (1.10 g)having the following physical data was obtained.

TLC: Rf 0.27 and 0.37 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.47–7.23 (m, 5H), 6.41 and 6.22 (each brd, J=10.2 Hz,totally 1H), 5.68–5.50 and 5.23–5.00 (each m, totally 1H), 5.36 and 5.07(each d, J=12.0 Hz, totally 2H), 5.16 (s, 1H), 4.88–4.64 (m, 1H),4.45–4.28 (m, 1H), 4.14–4.02 (m, 1H), 1.85–1.30 (m, 6H), 1.03–0.78 (m,21H), 0.15, 0.13, 0.05and 0.03 (each s, total 6H)

REFERENCE EXAMPLE 29(2S)-N-[(2S)-4-methyl-1-(5-methylthio-1,2,4-oxadiazol-3-yl)-1-(t-butyldimethylsilyloxy)-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

To a solution of the compound prepared in Reference Example 28 (347 mg)in N,N-dimethylformamide (3 ml) was added methyl iodide (45 μl) and themixture was stirred for 1 hour at room temperature. The reaction mixturewas poured into water and was extracted with ethyl acetate, washed withsaturated aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate and was concentrated. The residue was purified bycolumn chromatography on silica gel (n-hexane: ethyl acetate=4:1) togive the title compound having the following physical data.

TLC: Rf 0.61 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 7.43–7.25 (m, 5H), 6.57 and 6.21 (each brd, J=8.7 Hz,totally 1H), 5.25 and 5.17 (each brd, J=8.4 Hz, totally 1H), 5.09 (s,2H), 4.90–4.81 (m, 1H), 4.51–4.25 (m, 1H), 4.24–4.06 (m, 1H), 2.73 and2.69 (each s, totally 3H), 1.80–1.30 (m, 6H), 1.20–1.10 and 1.05–0.88(each m, totally 21H), 0.15–0.00 (m, 6H).

REFERENCE EXAMPLE 30(2S)-N-[(2S)-4-methyl-1-(5-methylthio-1,2,4-oxadiazol-3-yl)-1-hydroxy-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

To a solution of the compound prepared in Reference Example 29 (310 mg)in tetrahydrofuran (1 ml) was added t-butyl ammonium fluoride (1.0Mtetrahydrofuran solution, 0.79 ml) at room temperature and the mixturewas stirred for 30 minutes. The reaction mixture was concentrated. Theresidue was purified by column chromatography on silica gel(n-hexane:ethyl acetate=1:1) to give the title compound (242 mg) havingthe following physical data.

TLC: Rf 0.16 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 7.42–7.24 (m, 5H), 6.65 and 6.31 (each brd, J=9.3 Hz,totally 1H), 5.20–5.00 (m, 1H), 5.09 (s, 2H), 4.83 (brs, 1H), 4.63–4.50and 4.43–4.32 (each m, totally 1H), 4.17–4.03 (m, 1H), 2.71 and 2.70(each s, totally 3H), 2.48–2.39 (m, 1H), 1.80–1.36 (m, 6H), 1.02–0.80(m, 12H).

EXAMPLE 16(2S)-N-[(2S)-4-methyl-1-(5-methylthio-1,2,4-oxadiazol-3-yl)-1-oxo-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

By the same procedure as described in Example 1 using the compoundprepared in Reference Example 30 in place of the compound prepared inReference Example 11, the compound of the present invention having thefollowing physical data was obtained.

TLC: Rf 0.34 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 7.45–7.24 (m, 5H), 6.53 (brd, J=6.3 Hz, 1H), 5.46–5.35(m, 1H), 5.26–5.03 (m, 1H), 5.12 (s, 2H), 4.31–4.10 (m, 1H), 2.79 (s,3H), 1.82–1.42 (m, 6H), 1.09–0.84 (m, 12H).

EXAMPLE 16 (1) TO EXAMPLE 16 (9)

By the same procedure as described in Example 16 using the compoundcorresponding to the compound prepared in Reference Example 30, thecompounds of the present invention having the following physical datawere obtained.

EXAMPLE 16 (1)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[4-methyl-1-(5-methylthio-1,2,4-oxadiazol-3-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.29 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.73 (d, J=6.6 Hz, 2H), 7.53–7.38 (m, 3H), 7.23 (brd,J=7.8 Hz, 1H), 6.21 (brd, J=7.5 Hz, 1H), 5.42 (m, 1H), 4.31 (m, 1H),2.88 (m, 1H), 2.78 (s, 3H), 2.20–1.40 (m, 1H), 0.90 and 0.83 (each d,J=6.3 Hz, each 3H).

EXAMPLE 16 (2)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[4-methyl-1-(5-(1-methylethylthio)-1,2,4-oxadiazol-3-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.20 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃) δ 7.81–7.74 (m, 2H), 7.53–7.38 (m, 3H), 7.23 (brd, J=7.8 Hz,1H), 6.21 (d, J=8.1 Hz, 1H), 5.50–5.39 (m, 1H), 4.37–4.26 (m, 1H),4.11–3.95 (m, 1H), 2.86 (q, J=5.1 Hz, 1H), 2.17–1.40 (m, 11H), 1.52 (d,J=6.6 Hz, 6H), 0.90 and 0.85 (each d, J=6.3 Hz, totally 6H).

EXAMPLE 16 (3)(2S)-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,2,4-oxadiazol-3-yl)-1-oxo-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide

TLC: Rf 0.49 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 7.45–7.27 (m, 5H), 6.53 (brd, J=7.5 Hz, 1H), 5.47–5.38(m, 1H), 5.22–5.04 (m, 1H), 5.12 (s, 2H), 4.29–4.17 (m, 1H), 4.10–3.95(m, 1H), 1.82–1.42 (m, 6H), 1.52 (d, J=6.9 Hz, 6H), 1.03–0.86 (m, 12H).

EXAMPLE 16 (4)1-[1-(4-dimethylaminomethylbenzoylamino)cyclohexyl]-N-[4-methyl-1-(5-(1-methylethylthio)-1,2,4-oxadiazol-3-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.38 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.93 (d, J=6.9 Hz, 1H), 7.74 (d, J=8.4 Hz, 2H), 7.43 (d,J=8.4 Hz, 2H), 6.06 (s, 1H), 5.39–5.32 (m, 1H), 4.06–3.97 (m, 1H), 3.52(s, 2H), 2.37–2.18 (m, 2H), 2.28 (s, 6H), 2.06–1.95 (m, 2H), 1.86–1.32(m, 9H), 1.51 (d, J=6.9 Hz, 6H), 1.00 (d, J=6.0 Hz, 3H), 0.95 (d, J=6.0Hz, 3H).

EXAMPLE 16 (5)1-[1-(4-morpholinomethylbenzoylamino)cyclohexyl]-N-[4-methyl-1-(5-(1-methylethylthio)-1,2,4-oxadiazol-3-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.55 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.93 (d, J=7.2 Hz, 1H), 7.73 (d, J=8.4 Hz, 2H), 7.44 (d,J=8.4 Hz, 2H), 6.04 (s, 1H), 5.39–5.32 (m, 1H), 4.06–3.97 (m, 1H), 3.72(t, J=4.5 Hz, 4H), 3.55 (s, 2H), 2.45 (t, J=4.5 Hz, 4H), 2.36–2.18 (m,2H), 2.04–1.96 (m, 2H), 1.77–1.26 (m, 9H), 1.51 (d, J=6.6 Hz, 6H), 1.00(d, J=6.0 Hz, 3H), 0.95 (d, J=6.0 Hz, 3H).

EXAMPLE 16 (6)1-[1-(pyridin-3-ylcarbonylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,2,4-oxadiazol-3-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.41 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 9.00 (d, J=1.8 Hz, 1H), 8.77 (dd, J=4.8, 1.8 Hz, 1H),8.12 (dt, J=7.8, 1.8 Hz, 1H), 7.70 (d, J=7.2 Hz, 1H), 7.43 (dd, J=7.8,4.8 Hz, 1H), 6.16 (s, 1H), 5.41–5.34 (m, 1H), 4.06–3.97 (m, 1H),2.34–2.19 (m, 2H), 2.08–1.98 (m, 2H), 1.81–1.26 (m, 9H), 1.51 (d, J=6.6Hz, 6H), 1.01 (d, J=6.0 Hz, 3H), 0.98 (d, J=6.0 Hz, 3H).

EXAMPLE 16 (7)1-(1-morpholinocarbonylaminocyclohexyl)-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,2,4-oxadiazol-3-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.43 (n-hexane:ethyl acetate=1:3);

NMR (CDCl₃): δ 8.04 (d, J=6.9 Hz, 1H), 5.36–5.30 (m, 1H), 4.45 (s, 1H),4.07–3.98 (m, 1H), 3.72 (t, J=4.8 Hz, 4H), 3.39 (t, J=4.8 Hz, 4H),2.18–1.26 (m, 13H), 1.52 (d, J=6.6 Hz, 6H), 1.00 (d, J=6.0 Hz, 3H), 0.95(d, J=6.0 Hz, 3H).

EXAMPLE 16 (8)1-[1-(pyridin-4-ylcarbonylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,2,4-oxadiazol-3-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.51 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 8.78 (dd, J=4.5, 1.5 Hz, 2H), 7.62–7.60 (m, 1H), 7.61(dd, J=4.5, 1.5 Hz, 2H), 6.14 (s, 1H), 5.41–5.34 (m, 1H), 4.06–3.97 (m,1H), 2.33–2.29 (m, 1H), 2.22–2.17 (m, 1H), 2.07–1.99 (m, 2H), 1.82–1.24(m, 9H), 1.51 (d, J=6.6 Hz, 6H), 1.01 (d, J=6.0 Hz, 3H), 0.96 (d, J=6.0Hz, 3H).

EXAMPLE 16 (9)1-cyclohexyl-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,2,4-oxadiazol-3-yl)-1-oxo-2-pentyl]carboxamide

TLC: Rf 0.66 (n-hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 6.00 (d, J=7.8 Hz, 1H), 5.51–5.44 (m, 1H), 4.08–3.99 (m,1H), 2.22–2.12 (m, 1H), 1.89–1.19 (m, 13H), 1.53 (d, J=6.9 Hz, 3H), 1.52(d, J=6.9 Hz, 3H), 1.03 (d, J=6.0 Hz, 3H), 0.95 (d, J=6.0 Hz, 3H).

FORMULATION EXAMPLE FORMULATION EXAMPLE 1

The following components were admixed in a conventional method andpunched out to give 100 tablets each containing 50 mg of activeingredient.

(2S)-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4- 5.0 goxadiazol-2-yl)]-1-oxo-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide carboxymethylcellulose calcium (disintegratingagent) 0.2 g magnesium stearate (lubricant) 0.1 g microcrystallinecellulose 4.7 g

FORMULATION EXAMPLE 2

The following components were admixed in a conventional method. Thesolution was sterilized in conventional method, placed 5 ml portionsinto ampoules and freeze-dried to give 100 ampoules each containing 20mg of the active ingredient.

(2S)-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4- 2.0 goxadiazol-2-yl)]-1-oxo-2-pentyl]-2-benzyloxycarbonylamino-4-methylpentanamide mannitol 20 g distilled water 500 ml

1. An oxadiazole compound of formula (I),

wherein R is

R¹⁶ is CycA wherein CycA is mono-, bi- or tri-cyclic C3–15 carboring AA¹is a single bond AA² is

wherein R⁴⁸ is hydrogen, C1–4 alkyl, phenyl or C1–4 alkyl substitutedwith phenyl CycD is a C3–14 mono- or bi-cyclic carboring, R⁷ and R⁸ arethe same or different to represent (i) hydrogen, (ii) C1–8 alkyl, or(iii) C1–8 alkyl substituted with 1–5 of groups selected from thefollowing (1)˜(7): (1) —NR⁶¹R⁶², (2) —OR⁶³, (3) —SR⁶⁴, (4) —COR⁶⁵,(5)-NR⁶⁶CONR⁶¹R⁶², (6) CycA, (7)-NR⁶⁶SO₂R⁶¹, R⁶¹, R⁶², R⁶³, R⁶⁴ and R⁶⁶are the same or different to represent hydrogen, C1–4 alkyl, phenyl orC1–4 alkyl substituted with phenyl, R⁶⁵ is C1–4 alkyl, phenyl, —NR⁶¹R⁶²,wherein all symbols are the same meanings as above, —OR⁶³, wherein R⁶³is the same meaning as above, or C1–4 alkyl substituted with phenyl, R⁹is hydrogen, C1–8 alkyl, phenyl or C1–8 alkyl substituted with phenyl

R¹⁰ is (i) C1–8 alkyl, (ii) C2–8 alkenyl, (iii) CycA, (iv) —COR⁷¹ or (v)C1–8 alkyl substituted with 1–3 of group selected from CycA, —COR⁷¹,—NR⁷²R⁷³, —OR⁷⁴, cyano or —P(O)(OR⁷⁸)₂, wherein R⁷¹ is (1) C1–4 alkyl,(2) C1–4 alkoxy, (3) CycA, (4) —O-CycA, (5) —NR⁷²R⁷³, (6) C1–4 alkylsubstituted with CycA, (7) C1–4 alkoxy substituted with CycA, or (8)hydroxy, R⁷² and R⁷³ are the same or different to represent hydrogen,C1–8 alkyl, CycA or C1–8 alkyl substituted with CycA, R⁷⁴ is (1)hydrogen, (2) C1–8 alkyl, (3) CycA, (4) C1–8 alkyl substituted with—SiR⁷⁵R⁷⁶R⁷⁷, wherein R⁷⁵, R⁷⁶ and R⁷⁷ are the same or different torepresent C1–8 alkyl, phenyl or C1–8 alkyl substituted with phenyl, or(5) C1–8 alkyl substituted with CycA, R⁷⁸ is C1–8 alkyl, phenyl, or C1–8alkyl substituted with phenyl; and, CycA's included in R¹⁰ and R¹⁶ arethe same or different and CycA and CycD, independently, may besubstituted with 1–5 of R²⁷: R²⁷ is (1) C1–8 alkyl, (2) halogen, (3)—NR¹¹R¹², (4) —OR³, (5) a C5–10 mono- or bi-cyclic carboring, (6) nitro,(7) CF₃, (8) cyano, (9) —SR¹⁴, (10) —COR¹⁵, (11) oxo, (12) —SO₂R¹⁵, (13)—OCF₃, or (14) C1–8 alkyl substituted with 1–5 of group selected fromthe following (a)˜(k): (a) halogen, (b) —NR¹¹R¹², (c) —OR¹³, (d) a C5–10mono- or bi-cyclic carboring, (e) nitro, (f) CF₃, (g) cyano, (h) —SR¹⁴,(i) —COR¹⁵, (j) —SO₂R¹⁵, or (k) —OCF³, wherein R¹¹ and R¹² are the sameor different to represent hydrogen, C1–4 alkyl, —COO-(C1–4 alkyl),phenyl or C1–4 alkyl substituted with phenyl, R¹³ and R¹⁴ are the sameor different to represent hydrogen, C1–4 alkyl, phenyl or C1–4 alkylsubstituted with phenyl, R¹⁵ is C1–4 alkyl, phenyl, —NR¹¹R¹², whereinall symbols are the same meanings as above, —OR¹³ wherein R¹³ is thesame meaning as above, or C1–4 alkyl substituted with phenyl or anon-toxic salt thereof.
 2. The compound according to claim 1, whereinAA² is

J⁶ and Y⁶ are the same or different to represent a single bond or C1–3alkylene (with proviso that J⁶ and Y⁶ do not represent a single bond atthe same time), J⁷ is C1–6 alkylene, J⁹ is C1–3 alkylene, and each ringmay be substituted with 1–5 of R²⁷, and R²⁷ in CycA is (1) C1–8 alkyl,(2) halogen, (3) —NR¹¹R¹², (4) —OR¹³, (5) phenyl, (6) nitro, (7) CF₃,(8) cyano, (9) —SR¹⁴, (10) —COR¹⁵, (11) oxo, or (12) C1–8 alkylsubstituted with 1–5 group selected from the following (a)˜(i): (a)halogen, (b) —NR¹¹R¹², (c) —OR¹³, (d) phenyl, (e) nitro, (f) CF₃, (g)cyano, (h) —SR¹⁴, or (i) —COR¹⁵, wherein all symbols are the samemeanings as above, and R¹⁰ is (i) C1–8 alkyl, (ii) CycA, (iii) —COR⁷¹ or(iv) C1–8 alkyl substituted with CycA, —COR⁷¹, —NR⁷²R⁷³ or —OR⁷⁴ whereinall symbols are the same meanings as defined in claim 1, or a non-toxicsalt thereof.
 3. The compound according to claim 1, wherein R¹⁰ is C1–8alkenyl, or C1–8 alkyl substituted with 1–3 group selected from CycA,COR⁷¹, NR⁷²R⁷³, OR⁷⁴, cyano or P(O)(OR⁷⁸)₂ (with proviso that thesubstituent is one, then it is not CycA, COR⁷¹, NR⁷²R⁷³, or OR⁷⁴), or anon-toxic salt thereof.
 4. The compound according to claim 1, which is(1)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide,(2)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide,(3)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[(2S)-1-(5-benzylthio-1,3,4-oxadiazol-2-yl-4-methyl-1-oxo-2-pentyl]carboxamide,(4)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[(2S)-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-hexyl]carboxamide,(5)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[2S)-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-4-phenyl-2-butyl]carboxamide,(6)1-[(1R,2S)-2-(naphthalen-2-ylcarbonylamino)cyclohexyl]-N-[2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl],(7)1-[(1R,2S)-2-(4-methoxybenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide, (8)1-[(1R,2S)-2-(4-nitrobenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide,(9)1-[(1R,2S)-2-(4-chlorobenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide, (10)1-[(1R,2S)-2-(4-phenylbenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide, (11)1-[(1R,2S)-2-(4-fluorobenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide,(12)1-[(1R,2S)-2-(4-t-butylbenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide, (13)1-[(1R,2S)-2-(2-fluorobenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide,(14)1-[(1R,2S)-2-(4-cyanobenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide,(15)1-[(1R,2S)-2-(4-dimethylaminobenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide,(16)1-[(1R,2S)-2-(4-fluorobenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide,(17)1-[(1R,2S)-2-(4-chlorobenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide,(18)1-[(1R,2S)-2-(4-methoxybenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide,(19)1-[(1R,2S)-2-(4-cyanobenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide,(20)1-[(1R,2S)-2-(4-dimethylaminobenzoylamino)cyclohexyl]-N-[2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide,(21)1-[(1R,2S)-2-(N-benzoyl-N-methylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide, (22)1-[(1R,2S)-2-(4-dimethylaminomethylbenzoylamino)cyclohexyl]-N-[4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide,(23) 1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[(2S)-4-methyl-1-(5-t-butoxycarbonylmethylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide,(24)1-[(1R,2S)-2-(4-dimethylaminomethylbenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide,(25)1-[(1R,2S)-2-(4-dimethylaminomethylbenzoylamino)cyclohexyl]-N-[4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide,(26)1-[(1R,2S)-2-(4-dimethylaminomethyl-2-fluorobenzoylamino)cyclohexyl]-N-[4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide,(27)1-[(1R,2S)-2-(4-dimethylaminomethyl-2-fluorobenzoylamino)cyclohexyl]-N-[4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide,(28)1-[(1R,2S)-2-benzoylaminocyclopentyl]-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide,(29)1-[(1R,2S)-2-benzoylaminocyclopentyl]-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide,(30)1-[(1R,2S)-2-(2-dimethylaminomethylbenzoylamino)cyclohexyl]-N-[4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide,(31)1-[(1R,2S)-2-(2-dimethylaminomethylbenzoylamino)cyclohexyl]-N-[4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide,(32)1-[(1R,2S)-2-(3-dimethylaminomethylbenzoylamino)cyclohexyl]-N-[4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide,(33)1-[(1R,2S)-2-(3-dimethylaminomethylbenzoylamino)cyclohexyl]-N-[4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide,(34)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[1-(5-(2-dimethylaminoethylthio)-1,3,4-oxadiazol-2-yl)-4-methyl-1-oxo-2-pentyl]carboxamide,(35)1-[(1R,2S)-2-(2-dimethylaminomethyl-4-fluorobenzoylamino)cyclohexyl]-N-[4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide,(36)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[3-cyclopropyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-propyl]carboxamide, (37)1-[(1R,2S)-2-(2-dimethylaminomethyl-4-fluorobenzoylamino)Cyclohexyl]-N-[4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide,(38)1-benzoylaminocyclohexyl-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide,(39)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[2-(5-methylthio-1,3,4-oxadiazol-2-yl)-2-oxoethyl]carboxamide,(40)1-[(1R,2S)-2-(4-dimethylaminomethyl-3-fluorobenzoylamino)cyclohexyl]-N-[4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide,(41)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[2S)-4-methoxy-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-butyl]carboxamide,(42)1-benzoylaminocyclohexyl-N-[(2S)-4-methyl-1-(5-methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide, (43)1-[(1R,2S)-2-(4-dimethylaminomethyl-2-fluorobenzoylamino)cyclohexyl]-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide,(44)1-[(1R,2S)-2-benzoylaminocyclohexyl]N-[2S)-4-methoxy-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-butyl]carboxamide, (45)1-(1-benzoylaminocyclohexyl)-N-[(2S)-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-hexyl]carboxamide,(46)1-[1-(4-dimethylaminomethylbenzoylamino)cyclohexyl]-N-[4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide,(47)1-[1-(3-dimethylaminomethylbenzoylamino)cyclohexyl]-N-[4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide,(48)1-(1-benzoylaminocyclohexyl)-N-[1-(5-(2-dimethylaminoethylthio)-1,3,4-oxadiazol-2-yl)-4-methyl-1-oxo-2-pentyl]carboxamide, (49)1-[1-(4-dimethylaminomethylbenzoylamino)cyclohexyl]-N-[1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-hexyl]carboxamide, (50)1-[1-(2-dimethylaminomethylbenzoylamino)cyclohexyl]-N-[4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide,(51)1-(1-benzoylaminocyclopentyl)-N-[(2S)-4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide,(52)1-[1-(4-dimethylaminomethylbenzoylamino)cyclopentyl]-N-[4-methyl-1-(5-(1-methylethylthio)-1-oxo-1,3,4-oxadiazol-2-yl)-2-pentyl]carboxamide,(53)1-[(1R,2S)-2-(4-(2-dimethylaminoethyl)benzoylamino)cyclohexyl]-N-[4-methyl-1-(2-(1-methylethylthio)-1,3,4-oxadiazol-5-yl)-1-oxo-2-pentyl]carboxamide,(54)1-[1-(4-(2-dimethylaminoethyl)benzoylamino)cyclohexyl]-N-[4-methyl-1-(5-(1-methylethylthio)-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide,(55)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[(2S)-1-(2-cyclohexylthio-1,3,4-oxadiazol-5-yl)-4-methyl-1-oxo-2-pentyl]carboxamide, (56)1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[1-(2-(3-dimethylaminopropylthio)-1,3,4-oxadiazol-5-yl)-4-methyl-1-oxo-2-pentyl]carboxamide,(57)1-(1-benzoylaminocyclohexyl)-N-[4-methyl-1-(2-(3-dimethylaminopropylthio)-1,3,4-oxadiazol-5-yl)-1-oxo-2-pentyl]carboxamide,(58)1-(1-benzoylaminocyclohexyl)-N-[(2S)-1-(2-cyclohexylthio-1,3,4-oxadiazol-5-yl)-4-methyl-1-oxo-2-pentyl]carboxamideor (59)1-(1-benzoylaminocyclohexyl)-N-[(2S)-1-(2-benzylthio-1,3,4-oxadiazol-5-yl)-4-methyl-1-oxo-2-pentyl]carboxamide,or a non-toxic salt thereof.
 5. The compound according to claim 1, whichis1-[(1R,2S)-2-benzoylaminocyclohexyl]-N-[(2S)-4-methyl-1-(5-bis(methoxycarbonyl)methylthio-1,3,4-oxadiazol-2-yl)-1-oxo-2-pentyl]carboxamide, or a non-toxic saltthereof.
 6. A pharmaceutical composition comprising an oxadiazolecompound of formula (I) according to claim 1 or a non-toxic salt thereofand a pharmaceutically acceptable vehicle.